BIOVIA Discovery Studio

3DS.COM/BIOVIA3DS.COM/BIOVIA © © DassaultDassault Systèmes Systèmes| |Confidential Confidential InformationInformation | |3/16/2019 3/16/2019| BIOVIA Discovery COMPREHENSIVE MODELING COMPREHENSIVE 創源生技 FOR LIFE LIFE SCIENCES FOR AND SIMULATIONS AND 經理陳冠文分子視算中心 Studio (Gene) 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Copyright and Disclaimer Copyright • Copyright © • • • business relationship,disclosedpartiesthirdbe shall to not and confidential proprietaryor information of GGACorp.. shall It be used only the for purpose furtheringof our addition,informationIn presentation disclosedthis related in and documents,written,whetherisor oral shallwritten onlyresult a agreementfrom executedboth parties. by obligation upon GGACorp., and shall not be relied upon in purchasing anyproduct. Any such obligation The presentation, documents or anyrelated statements are not intended to, nor shall, create anylegal create, developlicense or anyproduct Enhancements. or Accordingly,representation,makingGGAno isCorp. undertaking commitmentlegalobligation no or to "Enhancements").plansexpectations Our or discretion. areourchange subject at time any to at future features, enhancements for functionalitiesfuture products or (collectivelycurrentor of presentationThis related and/or documents any contains statements regardingexpectationsplansor our 2019 2019 GGA corp. All rights reserved. rights All corp. GGA . Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | GGA ( Group BIONET the of part is Main Product & Service Areas:Main Product Service & Nov. Established: 2008 ChristopherCEO: Tsai, Ph.D. Stock Ticker: 4160 (TaiwanStock4160 Ticker: OTC) IPO Date:September 2012 17, 3. 2. 1. Scientific Informatics Informatics Scientific & Bio IT Diagnosis Molecular TestingGenetic 蔡政憲博士訊聯生物科技) Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 10 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | sustainable society chnology Combining company a About About Scientific and Science, Te Art for a for Dassault • • • passionate people 12,400 solutions Game changingGame 53 labsOne global R&D/ 112 nationalities 3D Systèmes EXPERIENCE • • • customers 190,000 >100 million online users online million>100 on premise users >10 million 12 industries140 in countries enterprise • • • partners 3,500 Sales& Services Technology Software & Education Research & Copyright©2019 Copyright©2019 • • • driven Long- Operating margin: 31.5%* : Revenue shareholder control Majority GGA GGA Corp., All reserved. rights term $ 2.8 Bn * * Non- IFRS 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | BIOVIADiscovery Perfect experimentally complicated, or risky to synthesize samples that may be too expensive, Rapidly test and validate virtual material Breakthrough silico in and ingredients newmaterials Discover Materials Validate to enhance to enhance offeringsnew product avoid IP conflicts IP avoid and leads, new find to molecules Rapidlyscreen largevolumes of 2 3 1 Discovery Perfect Molecules Screen Candidate Manufacture Performance & Optimize for Sustainable Copyright©2019 Copyright©2019 requirements trade and optimize performance, Link chemical structure and - offs between multiple multiple between offs GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Agenda • • 小分子化合物接合模擬 • • • • DiscoveryStudio: Receptor to Introduction Predictive Science Hands Hands Solution Macromolecule and Molecules Small Industry Science Life the of Challenges -on -on 操作教學基本介面操作教學 (實機演練) (實機演練) - Ligand Interactions Ligand Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Selection Disease Disease Identification Life Sciences R&D TopR&D Sciences Life Workflow Level Target Target Validation Target Target Target and ID Validation Development Screen Screen Hit ID Conjugate Molecule Biologic Small Hit Validation “Hitto Lead” Development PreClinical Optimisation” Copyright©2019 Copyright©2019 “Lead “Lead GGA GGA Corp., All reserved. rights and ADQM To Clinical Development “Preclinical” 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Chemist “Making” Small Molecule Small synthesizes the molecule the synthesizes Biotherapeutics Versus Is Different Extensive experimentation, random variation and variation random experimentation, Extensive Biological systems Biological screening intrinsic to the process the to intrinsic screening Biotherapeutics make the molecule the make Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights Intensive! Biotherapeutic 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Inoculation and tissue harvest Development To To Animal Lab Create display library candidatesDevelopment to fAb phage and Predictive Sciences can formulation, SEC retention Record purificationdetails, improve quality expressionlevels, buffer time, % main peak time,% reduce cycles Identify soluble Purify Purify Discovery is Molecular Biology Lab Molecular fAbs Ab 12-20 weeks 12-20 weeks of of Select bind to target (ELISA) Scale up top performing performing uptop Scale fAbs that that clones Sequencing Facility Labor Sequence fAbs and Time measurements Kinetics and Kinetics Affinity Affinity withbinding data clones, test bindingclones, totest cell lines that express Select top expressing sequence data Associate Associate Measure expression of LC and of HC by the target batch/clone Cell CultureCell Lab multiple cycles multiple 9 Optimization: 12 months -12 months Create fulllengthLC or more Transfect HEK cells Copyright©2019 constructs, store store constructs, constructs, track track constructs, and HC plasmidand HC batch IDs(HEK w selected clones) these GGA Corp., reserved. rights All Analytical Lab Analytical clones thatmatch Select andstore Transfect E. coli w plasmids, harvest sequences conceptual and lyse Sequence the LC the Sequence and HC from these clones these 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | • “The right target, the right exposure, the right drug” mission to bring life bring to mission approach drugto research anddevelopment. At AstraZeneca, more effective drugs. Sciences population, Example: AstraZeneca Example: Sciences… Pharma Improve Quality Improve – we’redoubling our investment in Predictive so we can tackleillnessso we anddisease witheven we’re spearheading the model - changing medicines to the global Save Money And Predictive And Predictive , Save TimeSave In our - based , 16 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Biotherapeutics DevelopmentChallenges • BIOVIA Sciences Predictive Purification Problems Examples of Developmentfailures in include: Immunogenicity Can Help to to Help Can Failures AvoidDevelopment Costly Low thermal stability Can Help Identify These Problems Earlier Problems These Identify Help Can Poor solubility/ Poor stability Poor serum halfserum Poor Copyright©2019 High viscosity High GGA Corp., reserved. rights All - life life 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Generationalchanges 3DEXPERIENCEwith Copyright©2019 GGA Corp., reserved. rights All 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | SimulationLife & Modeling Multiscale Vision: cells, interactions which apprehend HOLISTIC and aims their & between the at INTERDISCIPLINARY understanding interaction complexity components with of the biological of the spatio a approach environment cell, - temporal between systems to . Copyright©2019 GGA Corp., reserved. rights All 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | What’s Discovery Studio Discovery What’s Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Discovery Studio: A ComprehensiveDiscoveryA Studio: Portfolio aggregation Specialist: Specialist: Stability Stability Binding Binding Protein Protein affinity Protein and and Membrane Membrane Specialist: Specialist: Specialist: Specialist: docking Antibody Antibody Proteins Protein Protein design Mechanics Simulation Homology modeling Quantum Quantum X and - ray In screening enumera hopping - Scaffold Scaffold Virtual situ tion lead lead Copyright©2019 Copyright©2019 - GGA GGA Corp., All reserved. rights ADME and and ADME profiling Toxicity QSAR, Ligand Ligand 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | 3. 2. 1. includes: tool design Protein 3. 2. 1. 6. 5. 4. Benefit Optimize protein Optimize prediction Epitope stage preparation sample efficiency in the Increase … Virtual mutation aggregation Protein pH detection epitope and docking Protein Advanced homology tools modeling based protonation protonation -based Structure Design of of Design Biologics Rational Rational - Based Protein Protein design Chemical Chemical integration design Data Copyright©2019 Copyright©2019 Modelling ToolsModelling Molecular Automatic Data Formats Support Different GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Science and Functionality Highlights andFunctionality Science • • • • • • • • • • • • • Humanization Disulfide risk aggregation Managing stabilityprotein and guiding Predicting protein Optimizing detection epitope and docking Protein Antibody loop Antibodyfor tools Specialist Implicit explicitsolvent or verificationmodel Rigorous Advanced homology and analysis alignment Sequence Template identification bridge modeling prediction - protein bindingprotein affinity modeling - based MD simulations based and refinementand modeling tools Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Template Identification • • • Refine template selection Generatereports protein BLAST PSI or Blastusing PDBSearch the • • • Specify and filter and Specify byfilter species template a retrieved with problems potential Spot macromolecule for the target templates optimal Identify - Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | ‡ * Marti Sonnhammer - Renom Sequence Alignment and Analysis Alignment Sequence • • M.A., E. L., von von L., E. - post possible with associated motifs sequence Identify templates Align quickly sequences and accurately to • • • • • • • • • coefficient, extinction molar charge, molecular points, isoelectric as Additionally, such properties, biophysical calculate - in sites modification sequence from transmembrane Optionally, proteins in helices predict Align123 using sequences aligning Optionally, when matching structure secondary include Align123 sequences template align to alignment structure Use to the structure structure the profile to Madhusudhan translational Heijne * G., Krogh A. A. Krogh G., : Align model sequences sequences model Align : M.S., hydropathy ‡ , A. , A. Sali Proc. Conf. Int. biotherapeutics Protein Science, and Antigenic sites Antigenic and Intell . Syst.Biol. Mol., 2004, 13, 1071- 1087 1998, 6 , 175 Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | * † Spassov Webb B., Supplement5.6.1- 15, Advanced Homology , V.Z., • Sali A., A., Use theUse industry • • • Flook et al CHARMm using conformation -chain side Optimize loops Use LOOPER automatically of proteins models target homologyBuild , P.K., Yan, L. , 5.6.30 CurrentProtocols in Bioinformatics, John WileyInc.Sons, & Prot. Eng., Design & Selection, simulations * and CHARMM to refine refine to and CHARMM - standard MODELER Modeling , 21, 91- 2008, 21, 100 , 2006, Tools † Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | * Almagro J.C., et al Specialist Tools Antibody for Specialist • Bestclass in • • • • • • , Model refinements andsimulations refinements Model IMGT, using Annotate loops CDR model Accurately VL and VH Template identification structure Fv or Fab Full Proteins length IgG1 structure models structure IgG1 -length , 2011, 79(11),- 3050 domain (VHL) Framework models Framework (VHL) domain * mAb 3066 DOI: 10.1002/prot.23130 homology , Honegger or or Honegger , Chothia Modeling Modeling toolkit Kabat Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Specialist Tools Antibody for Specialist • PDB Antibody databases PDB Antibody Identify Templates in PDB or curated • • • • • templates for each chain, or or domain for chain, each templates optimal and identify Search IMGT, using: CDR andnumber loop Report HMM using domains constant and variable identify Automatically Filter by organism (human, mouse, etc.) mouse, (human, organism by Filter search template in regions CDR to exclude Ability , Chothia Kabat , Honegger , Modeling Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Specialist Tools Antibody for Specialist • sequence with templates withsequence Quickly and accurately modelalign • • • alignments on either light or heavy chains heavy or light on either alignments perform Simultaneously, independently but , Chothia IMGT, including numbering residue Using algorithms alignment sequence multiple and alignment structure multiple Using Kabat , Honegger , Modeling Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Rigorous Model Verification Model Rigorous • models Rigorouslyhomology validate • • • Ramachandran plots: plots: Ramachandran VerifyProtein (MODELER): VerifyProtein (Profiles3D): • • • Verify molecules protein a collection from of Select structure the best environment 3D its to a sequence of fitness the Evaluate Phi and Psi angle distributions angle Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Specialist Tools Antibody for Specialist • Use MODELER to build Use tobuild MODELER of antibodies: models homology • • Framework: Framework: structures IgG2 or from IgG1 models Build Length: Full • • Interface template to automaticallyInterface template to orientchains Developed in collaboration with alarge Pharma customer Light Chain Light Template Specify differentSpecify chain respectively light templates and heavychain for Interface Template Heavy Chain Template Modeling Template Chimeric Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | * Spassov , V.Z., , V.Z., Antibody Loop • • • Flook Build models based on based templates loop models Build loop each for template best the Find HMM using loops the CDR identify Automatically • • • • , P.K., Yan, L. Prot. Eng., Design & Selection, 2008 Selection, & Design Eng., Prot. L. Yan, P.K., , systematically search and optimize CDR loops optimize and search systematically Ab Initio Loop Refinement: structure Loop Grafting: Manual Filter byresults canonical typestructure Curated antibodydatabase Modeling , 21, 91 , 21, Copy loops from a template a template from loops Copy - 100 Use LOOPER* to LOOPER* Use and Refinement structure X -Ray Copyright©2019 Copyright©2019 Refinement Post GGA GGA Corp., All reserved. rights refinement Pre - 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | # ‡ † * Pierce B., B., Pierce Pierce B, B, Pierce R., Chen Chennamsetty Protein Docking and Epitope Detection and Epitope Docking Protein • • Weng Weng Weng Additionally, use -Antibody binding: Antigen Predict sites interaction -protein protein putative identify Z. Proteins,Z. • • N., N., Z. Proteins,Z. Z. Proteins,Z. Voynov possible docking poses docking possible and output patterns interaction protein ZRANK ZDOCK ZDOCK rankings V., V., 2003 , 67(4), 1078 67(4), , 2007 2008 Kayser , 52, 80 52, , , 72(1), 270 72(1), , V., V., ‡ *† Helk - : 87. : B., and Trout B.L., Proteins, Proteins,B.L., Troutand B., - Quickly andaccurately refine 279 - 1086 - protein search Comprehensively AggMap 2011 , 79, 888– , 79, # to quickly to 897 Antigen site A, G site G A, Protein Protein Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights Fc - Glycan receptor sites site 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | and stability and Virtual Mutagenesis: Predict mutation bindingeffect both for • • • • • protein ionization protein pH- generate Automatically for: easyit made interface andflexible user consistent Simple, Consider temperature Consider solution of strength ionic Consider • • • • • pH dependent mutation energies dependent mutation pH mutants for and dependent typepH for binding/stability wild properties electrostatics their studying protonation proper for the with structures mutant and type wild mutagenesis saturated Virtual Virtual alanine scanning (or any type residue of scanning) to take into account of account into take to dependent mutations multiple mutations mutations multiple X  [A W V … Y] D C solution pH solution X  Ala and Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | * Spassov Optimizing Protein , V.Z., • • to molecular topartners Evaluate the effect of point mutations on binding specific temperature or pH or temperature specific effectthe Calculate ata • • • Flook Or, full residue type scanning: X scanning: Or,type residue full Perform ‘ across 19 proteins 19 across for mutations point 380 single experimental onpublished Based , P.K., Yan, L. Prot. Eng., Design & Selection, Ala ΔΔG scanning’: X -scanning’: bind * energies energies - Protein Binding AffinityProtein , 21, 91- 2008, 21,  Ala  100 [A C D …V W Y] Gray = ExperimentalGray = Black = Calculated Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | * Proteins, Proteins, Chennamsetty Spatial Aggregation Propensity Aggregation Spatial • beyond Antibody formulations beyond Antibody Protein aggregation hotspots are useful for other applications • , 79, 888– 79, 2011, binding regions binding protein of prediction E.g., N., N., Voynov 897 V., Kayser V., Helk B., and Trout B.L., B., andTrout Antigen * E.g., – Other Uses Other region of an IgG1 antibodyregion3PGF]an IgG1 of [PDB: Antigen binding domain FABon the Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights FAB region 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | * B.L., Proteins, Proteins, B.L., Chennamsetty Spatial Aggregation Propensity Aggregation Spatial • EGF bindingEGF region beyond Antibody formulations beyond Antibody Protein aggregation hotspots are useful for other applications • E.g., prediction of protein binding regions binding protein of prediction E.g., , 79,2011, 888– N., N., Voynov V., V., 897 Kayser V., V., Helk B.,Trout and * – Other Uses Other E.g., (EGFR) [ (EGFR) epidermalgrowth factor receptor and self EGF Copyright©2019 Copyright©2019 Self PDB: 1IVO] - binding region - bindingdomains on GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Disulfide • • stereochemistry and factors such as: as: such and factors stereochemistry Disulfide disulfide predicting by aprotein, in stability Improve • • depth and residue mobility thermal clashes, Steric genuine Validated using bridge sites bridge bonds assessed for for good both assessed bonds Bridge Prediction Bridge disulfide ca. ca. bridges bridges 1,500 structures with 1,500 structures position reported by Kim by position reported successfullytesting, the engineered reproduces In DOI: 10.1002/bit.24371 DOI: Copyright©2019 Copyright©2019 et al al et in lipase B [PDB: 1TCA]lipase B in GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Antibody Humanization Workflow Humanization Antibody • • • Predict most stabilizing mutationshumanized stabilizing Predict most hotspots humanization residue Highlight sequences for humanizing mutations Search queryLight andHeavy chain antibody • • • • • • • automatically buildmodel a3D the Antibody Or,use Eitherpre- supplya Optionally, excludeand CDRVernier regions humanizingSee residues via not matchdo germlinesand frequency Sitesresidue less than where 5%occurs in Optionally,referencecompare to a sequence Search against reference germlinedatabases built antibody structureantibody model built Modeling ‘logo plots’ Cascade to Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Antibody Humanization Workflow Humanization Antibody Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Solution Component Mapping Chart ComponentMapping Solution Q N U N U S S E E I 10 0 This This mattersto biotherapeutics management to help These Nice to have Junk Cool, Cool, make a better biologic faster biologic bettera make CUSTOMER VALUECUSTOMER - multi pH mutation stabilitymutation pH Commodity / CoreCommodity / enhancement ** enhancement residue mutation mutation residue Differentiators Capability Capability Stability Prediction Stability Prediction Copyright©2019 pH Mutation Modeling – Antibody ** ** GGA Corp., reserved. rights All and Annotation Seq Analysis Analysis AggMap Predictor ** Predictor Disulphide Disulphide 10 Bond ** / DI 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Structure Design of of Design Biologics Rational Rational - Based Protein Protein design Chemical Chemical integration design Data Modelling ToolsModelling Molecular Automatic Data Formats Support Different 5. 4. 3. 2. 1. 5. 4. 3. 2. 1. includes: design tool Chemical Benefit Lead optimization Lead Target ( Screen Virtual High Throughput rate failure and cost the Reduce mechanism drug the Explore tools Toxicityand ADMET prediction tools design Library Fragment tools -based Ligand design Structure fishing vHTS - Copyright©2019 Copyright©2019 - based design tools based design based design tools based design ) GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Science and Functionality Highlights andFunctionality Science • • • • Structure Structure and Analysis Design Library Pharmacophore modelling Structure • • • • • • • • • Ligand Profiling Ligand Structure -based Ligand Filtering/Analysis Refinement/ Scoring/Prioritisation Fragment Docking QSAR and Machine Learning andMachine QSAR and Toxicology ADMET - Activity Activity based design -based based design -based Relationships Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 |

Scales Design Drug Small Rationale 10 10 10 10 ADMET andADMET Toxicity 3 0 Novel Derivatives ~10 0 2 ~10 ~10 ~10 7 Screening 2 Molecules fromMolecules 2 3 Library Molecules Pass Molecules Leads Molecules As Molecules Molecules as Molecules Fragment Structure - - ADMET and Toxicity and ADMET Analysis Analysisand Library Design based design based design Pharmacophore modeling Copyright©2019 Copyright©2019 What if the hit hit the What if (Side effects) (Side has multiple multiple has GGA GGA Corp., All reserved. rights targets? 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking & Scoring & Scoring Docking – - Structure Interactions Structure Ligand Based Design Binding Site on Receptor on Site Binding Receptor Structure Receptor Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | SBD: Input Preparation Input SBD: Proteins • • • • • • Calculate loops medium size Optimize short& loops missing Insert conformations Remove alternate residues Insert missing in atoms Standardise pK atom names and protonate Ligands • • • • • • • • • common groupscommon Standardize for charges Generate groupsfunctional Ionize Enumerate states ionization coordinates Calculate 3D Add Retain largest fragment bad valencies Fix Remove duplicates isomers hydrogens tautomers and Fragments • • Rule of Three filters RECAP* rules Generate fragments using Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | SBD: Fragment Modifying Scaffolds Probing the Binding Site Fragment Replace Replace REPLACE - Receptor De Novo Novo De Based Design Methods Design Based PLACE MCSS Evolution De Novo Novo De Link & & Link GROW Scaffold Grow Grow Alternative fragment Alternative • Fragment Based Pharmacophores Based Fragment Adding Fragments Copyright©2019 Copyright©2019 based methods available available methods -based Adding Fragments GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | SBD: Fragment • • REPLACE GROW • • • • • • E.g., scaffold situ in based Fragment Pre Ether Williamson Suzuki, Esterification, synthesis, Amide E.g., enumeration ligand situ in -based Reaction Pre filtered sets of reagents selected from from selected of sets reagents -filtered ACD filtered set of 1.5M fragments generated from SCD from generated fragments of 1.5M set -filtered hopping, R -hopping, - Based Design Methods Design Based isostere group replacement -group replacement Hiyama , Kuyama, Copyright©2019 Copyright©2019 Negishi GGA GGA Corp., All reserved. rights , Stille , 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 For| NCKU and NTHU Uses protein pocket to to pocket protein Uses Optional: Choose any Choose Optional: GROW: Reaction required interactions required perform reaction(s) perform guide selection guide Pick where to whereto Pick - Optional: Choose flexible Choose Optional: based residues in - situ Ligand Optimization Ligand Conformation sampling only Choose reaction scheme(s) violations, receptor bumps Copyright©2019 Copyright©2019 Choose reagent libraries and fragment ‘novelty’ Paretoresults sortby interactions, Lipinski or full minimization full or Optional: Choose GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Optional: Choose flexible Choose Optional: pocket selection guide pocket to Optional: Choose any Choose Optional: Optional: Use protein protein Use Optional: REPLACE: Fragment Based Fragment REPLACE: perform replacement perform required interactions required Pick where to whereto Pick residues In - Situ Substitution Choose fragmentlibrary types similaritypropertiescut + Conformation sampling only Optional: Choose fragment violations, receptor bumps Copyright©2019 Copyright©2019 and fragment ‘novelty’ Paretoresults sortby (Or supply(Or your own) interactions, Lipinski or full minimization full or Optional: Choose GGA GGA Corp., All reserved. rights - off 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | . vemurafenib Fragment PIM First fragment First - 1 IC 1 50 ~ 100μ M based drug ( drug -based - based design of the BRAF inhibitor inhibitor BRAF the of design based Zelboraf PIM - 1 IC 1 ) approved in 2011! in approved ) 50 > 100μ M Swen Hoelder, Paul A. Clarke, Paul Workman, Workman, Paul2012 Clarke, A. Paul Hoelder, Swen Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Pharmacophore Modelling Pharmacophore • • • • Ligand- generation Automaticmanual and features Customisable pharmacophore and 3D 2D based • • • • • Combination Shape -based Feature Fragment SMARTS based and structure- based and -based (Single & Multiple Ligands) Multiple & (Single Alignment Structure - - Based Based Copyright©2019 Copyright©2019 Automated Ligand Automated (QuantitativeQualitative) & Fragment GGA GGA Corp., All reserved. rights - Based - Based 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | - Ligand • • Automatic Manual • • • Bioactive ligand conformationligand Bioactive Quantitative Qualitative • • • • • Alignment Findsfeatures that relate to activity HypoGenRefine) predicativeSAR ( active ligands Findsfeatures set of similarlyshared bya features ( Common Based Pharmacophores HypoGen HipHop / / HipHopRefine) Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | - Structure • • Manual Automatic • • • • Fragment map Interaction site binding a from Interactions Receptor Based Pharmacophores Ligand complex -Ligand -based Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Ligand Profiling Ligand • • PharmaDB pharmacophores against multipleligands of libraries screen Rapidly • • • • • • • Classified using Kyoto Kyoto using Classified validated models14031 Derived thefrom Prof. with collaboration in Validated In drugs existing Repositioning/repurposing effects) (side off-drug protein Predicting silico * Kellenberger target fishing target scPDB Encyclopedia ( http://bioinfo et al et , J J Chem of Genes and Genomes (KEGG) Genomes and Genes of Rognan - Info Model Info pharma.u at University of Strasbourg* University of at , - 2006 strasbg.fr/scPDB targets -targets , 46 , 717 , - 727 - BRITE ) Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Library Design and Analysis Design Library • • • • • • • DS Application Edition (Pipeline Pilot) (Pipeline Edition DS Application Novel ligand generation - Multi selection Similarity Clustering selection Diversity Library enumeration • • • BREED Markush -based Reaction objective -based pareto optimization R1 N O Copyright©2019 Copyright©2019 O R2 GGA GGA Corp., All reserved. rights R1 N O R2 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Workflow of Virtual High Throughput Screening Screening WorkflowThroughput Virtual of High preparation design and and design Library Compounds 12,000,000 compound 10s per Preparation Protein Protein 120,000,000 Poses Docking 120,000,000s 120,000,000 = 1389 days= 1389 = 33,334h Poses Scoring Copyright©2019 Copyright©2019 Validation 1 Hits GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Workflow of Virtual High Throughput Screening Screening WorkflowThroughput Virtual of High Compounds Compounds 12,000,000 <500,000 preparation design and and design < 1 day < 1 Library compound 10s per Preparation Protein Protein 5,000,000 Poses Docking <5,000,000s 5,000,000 = 58 days= 58 = 1389h Poses Scoring Copyright©2019 Copyright©2019 Validation 1 Hits GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Compound databases Compound • BIOVIA database • • • • • • Metabolite Metabolite C Toxicity MDDR S A creening creening vailable vailable omprehensive omprehensive – – 239,064 registered structures with bioactivity data bioactivity with structures registered 239,064 172,542 registered structures structures registered 172,542 C C – hemicals hemicals ompounds ompounds 71,359 molecules within 119,425within molecules 71,359 reactions M edicinal edicinal D irectory D irectory C hemistry – 12,138,856 unique compounds unique 12,138,856 – 10,852,222 unique compounds unique 10,852,222 – 9603 registered structures structures 9603 registered Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | ACD Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Cluster subsets Cluster • • • • …. Countable propertymolecule of cluster molecule clusterDiversityof molecule ofNumber cluster steps sequential analysis the for time Save 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Reference Cluster subsets cont. cont. subsets Cluster • • Countable propertymolecule of cluster molecule clusterDiversityof + 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Predict compound properties by Statistic Statistic QSAR method: byproperties Predict compound 243.39 Descriptor Molecular MW • Q uantitative Chemical Data Chemical AlogP 5.601 Surface Area Surface 260.587 S tructure Dipole 0.662 N - … … A ctivity ctivity Correlation Define R

],  ) 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | • • Property calculation ADMET • • • • • • • • • ADMET and ToxicologyADMET Semi properties molecular 3Dand 2D rules SMARTSpublished on groups based function undesirable for molecules smallFiltersets of Hepatotoxicity CYP2D6 binding binding protein Plasma penetration barrier brain Blood solubility Aqueous absorption Human intestinal empirical and DFT and -empirical • Predictive ToxicologyPredictive • • • • • • • • • • • • • • • Log P Daphnia magna EC50 Fathead minnowLC50 Aerobic biodegradability Eye irritancy Skinirritancy and sensitization chronicRat LOAEL inhalationRat LC50 toxicity maximumtolerated Rat dose Rat oral LD50 Developmental toxicitypotential Carcinogenic potency TD50 Weight evidence of carcinogenicity FDA data) Rodent carcinogenicityand (NTP Ames mutagenicity Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | - Structure • • • • 3D molecular field 3D - Continuous data Categorical data and activity cliffs activity and (MMPs) transformations PairsMatched Molecular • • • • • Multiple Linear Regression Linear Multiple Squares Least Partial Approximation Function Genetic Partitioning Recursive Bayesian Activity Relationships (QSAR) Relationships Activity based Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Interface and Interface Architecture Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights • • • 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Client(s) Client(s) Server Pilot: Pipeline on runs science Studio Discovery • • • • • • • • DS engines DS collection AEP Collections PP Client AEP Web client PPDesigner Seat DS client Discovery ProductStudio Architecture DiscoveryStudio Client (Windows andLinux) CHARMm Protocol Protocol Protocol MODELER Discovery Studio Collection StudioDiscovery Pipeline Pilot Server Protocol (PPDesigner Seat) Pipeline Pilot Protocol Catalyst (Windows) Protocol Copyright©2019 CNX Protocol GGA Corp., reserved. rights All Protocol 3 Protocol rd Web Client Party 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Discovery ProductStudio Architecture Client Download results Get Authentication License server Pipeline pilot serverPipeline pilot Copyright©2019 GGA Corp., reserved. rights All 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Job window Job Toolbars and Menu Explorer Tools Explorer Protocols 3D view Supporting technology: Discovery Studio Client Studio Discovery technology: Supporting Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights Plot Ramachandran Sequence view Plots 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Discovery Studio Client Studio Discovery • General • • Monitors Display Style • • • • • • • RMSD Interactions Distance, and Bump Angle, Plane Clipping Shadow Surface Surface/Protein Ribbon Solid CPK, Stick, and Ball Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Discovery Studio Client Studio Discovery • • Protocols General • • • • • • Collaboration, presentation functions presentation Collaboration, plots data and functions Chart prediction structure Secondary view Sequence Perl scripting andcustomization Automation • • Story board, Active X board, Active Story maps. heat plot, point plots, Line etc Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Data integration Data • • • Create new one Create new from database Download fileOpen exist • • • • • • NCBI NCBI (PDB) Bank Data Protein format structure Protein format Sequence format structure Chemical Small molecule, DNA, RNA, Peptide RNA, DNA, molecule, Small Entrez Sequence Search Sequence Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Files Protocols Tools DS Client DS Client Hierarchy window - Windows Job windowJob Copyright©2019 Copyright©2019 Molecule windowMolecule Table window GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Atom display Display style Protein display Protein Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Atom display Atom Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Protein display Protein Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Display styleDisplay cont. Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Monitor and Non- and Monitor bond Interactions tools Interactions bond Distance Torsion Angle Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Monitor and Non- and Monitor bond Interactions tools Interactions bond Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 For| NCKU and NTHU Surface Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Overlay/Superimpose/RMSD Overlay/Superimpose/RMSD Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Hands- • Try to styledisplay as change the • • • • • • protein G( protein -2 gamma subunit G(I)/G(S)/G(O) protein R chain: R chain: chain: S C chain: -1 beta subunit G(I)/G(S)/G(T) protein chain: B A chain: 6n4b code: PBD on binding -binding nucleotide Guanine scFv16 -binding nucleotide Guanine Cannabinoid receptor 1 receptor Cannabinoid -binding nucleotide Guanine i -1 alpha subunit ) paper! Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Agenda • • 小分子化合物接合模擬 • • • • DiscoveryStudio: Receptor to Introduction Predictive Science Hands Hands Solution Macromolecule and Molecules Small Industry Science Life the of Challenges -on -on 操作教學基本介面操作教學 (實機演練) (實機演練) - Ligand Interactions Ligand Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking & Scoring & Scoring Docking – - Structure Interactions Structure Ligand Based Design Binding Site on Receptor on Site Binding Receptor Structure Receptor Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking & Scoring & Scoring Docking – - Pharmacophore Pharmacophores Structure Ligand Based Design Binding Site on Receptor on Site Binding Receptor Structure Receptor Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Ligand structure unavailable structure Ligand Ligand structure available structure Ligand Strategy for Small Molecule Drug Design Drug Molecule Small for Strategy • • • DockingScoring & Fragment De Receptor novo drug design • • pharmacophoredesign drug Structure Structure - baseddesign drug structure available - - based based baseddesign drug • • • Ligand- QSAR Library Receptor Design/ based structure unavailable Copyright©2019 Copyright©2019 drug design Analysis Diversity Analysis GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Ligand structure unavailable structure Ligand Ligand structure available structure Ligand Strategy for Small Molecule Drug Design Drug Molecule Small for Strategy • • • Fragment De Docking & Scoring Docking Receptor novo drug design • • pharmacophore drug design drug pharmacophore Structure Structure - baseddesign drug structure available - - based design drug based • • • Library Ligand- QSAR Receptor Design/ based structure unavailable Copyright©2019 Copyright©2019 drug design Analysis Diversity Analysis GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | - Structure • • • May needto identify the binding site is One approach identify to potential ligands thatcan bind to receptor Using knowledgeof areceptor guide of todesign new ligands • • • • • • Scoring of docked ligands Scoringof Rigid or flexible docking High use Can either an experimental or homologymodel Structure of the receptor is known Activesite search - throughput virtual screening throughput virtual Based Drug Design Drug Based Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking WorkflowDocking Protein & LigandsProtein & Validate Results Preparation Docking Scoring T hroughput Repeat Cycle= V irtual irtual ( vHTS S H creening igh igh ) • • Requirements very important. is steps each in phase evaluation the success, of therate maximize to In order • • • • proceeding the docking and scoring steps steps scoring and docking the proceeding before library in molecules the Prioritized technique docking parameters the of Optimize molecules Bound compounds active Known decoy and Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking WorkflowDocking Protein & LigandsProtein & Validate Results Preparation Docking Scoring Prepare Protein Prepare Ligand • • • • • • • • • Standardization charges Standardization Valence modification Remove duplicates Creating isomers 3D Generate coordinates structure atom hydrogenAdd protonation state the Modify site binding Identify structure deficient Repair Protein Preparation Protein Ligand Preparation Ligand Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | SBD: Input Preparation Input SBD: Proteins • • • • • • Calculate loops medium size Optimize short& loops missing Insert conformations Remove alternate residues Insert missing in atoms Standardise pK atom names and protonate Ligands • • • • • • • • • common groupscommon Standardize for charges Generate groupsfunctional Ionize Enumerate states ionization coordinates Calculate 3D Add Retain largest fragment bad valencies Fix Remove duplicates isomers hydrogens tautomers and Fragments • • Rule of Three filters RECAP* rules Generate fragments using Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Selecting the Protein Receptor Protein the Selecting • • • • Can be an Can three- a Requires Probably have a receptor in mind already protein the Choosing receptor • • • • • NMR structure X by data biological Reinforced problem medical or on biological Based Homology model -raycrystal structure apo formreceptor of dimensionalreceptor the structure of Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Protein Preparation Protein • • Preparation includesPreparation having... prepared must be properly the receptor can beperformed, Before any docking • • • • • Correct chemistry completed residues All Particularly a concern withPDB files Correct formal charges added atoms hydrogen required All • • Correct atom valences Correct bondorders Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Protonation state Protonation • • protonation status Example forProteinHis334ofdifferent in A Modify the protonation (ionization) statustheModify Calculate pKa for each residue in different in residue each for pH GLU1018 HIS2998 HIS2946 HIS2898 HIS2865 HIS2826 HIS2625 HIS2500 HIS2488 HIS2455 HIS2452 HIS2391 HIS1937 HIS1591 HIS1575 HIS1540 HIS1253 HIS376 HIS334 A Protein Copyright©2019 Copyright©2019 pH7.2 GGA GGA Corp., All reserved. rights 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 pH8.0 - 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Standardize molecules Standardize • Beautification • • • • • Center molecule (option of Standardize Molecule) of Standardize (option molecule Center of (option component) hydrogens Hydrogens hetero Add Add hydrogens Add/Remove in Utilities) (found numbers atom Add/Remove Molecule) Standardize of (option fragments largest/smallest Keep/Remove Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Standardize moleculesStandardize cont. • • • • Generate Salts Further components: Saltsparameter User via added be can queries saltdefined User Chemistry Data \ counter ions. its Salts Strip contains any defined salt structure will strip a parent will molecule of Queries Identify Salts Identify \ Salts.sd Salts.sd - Strip salts Strip and Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Ligand preparation preparation Ligand Performs the following steps, some of which can be controlled by be can which ofsteps, some followingPerforms the • • • • • • the protocol theparameters: given rangepH (Optional) a ionizationEnumerate at states Kekulize common functionalgroups on formalcharges Set standard fragment largest the onlyKeep tautomercanonical a Generate Enumerate the molecule tautomers (Optional) • • • • • • reasonable 3Dconformation reasonable Catalyst is used to generate a (Optional) conformation 3D a standard Generate (Optional) rules Filter thatviolate structures Lipinski (Optional) Removeduplicate structures enumerated are and atoms bonds unspecified only default By (Optional) isomers Enumerate Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | • Tautomers – – This means: tautomers atoms, but exist which easy and rapid equilibrium,in are called arrangementstructures of markedly whose Compounds indiffer Different structures may have different values for calculated properties. properties. calculated for values different have may structures Different may be molecules duplicate missed. Possible . H O N O N H 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Protein Reports and Utilities Tools andUtilities Reports Protein • Allows you to: • • • • • • • • • Fix connectivity Fix atoms missing Add molecules protein Clean molecules distinct into structures Split plots hydrophobicity Generate the protein about information Summarize sequences Renumber Define a template for a nonstandard amino acid amino for a a nonstandard Define template names Fix Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Binding Site Identification Site Binding • • • to be: - protein that and 1997 found Jones Thornton volumes: cleft of analysis Laskowski be: to sites binding molecule Liang 1998 et al. found small • • • • • Flat and hydrophobic and Flat others the than larger considerably is cleft largest the Usually cleft largest the in bound is ligand the Often site binding true the is largest often site the And cavities or crevices, Indentations, protein interaction sites tend sites interaction protein et al. 1996 reported an 1996reportedal. et Abl tyrosine kinase Copyright©2019 Copyright©2019 kinase kinase HSV GGA GGA Corp., All reserved. rights 1 thymidine -1 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Binding Site Identification Site Binding • • With unbound proteins… With unbound complexes... of ligand determination structure With experimental • • • • • not beobvious sitemayBinding candidates new sitesforlimit binding ligands possible toknown of position the Use featuresadditional show can Analogues identified often siteis Binding be sought sitemust Binding Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Binding Site Identification Site Binding • • Can be accomplished be accomplished Can When unknown… thesite binding is • • • with Binding Site Tool panel proteins similar to target Compare data experimental Use cavities for Search • • • NMR results NMR Cross - Site directed mutagenesis studies mutagenesis directed - linking data linking Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Site Search Approaches Search Site • Protein Shape • • crevices and cavities Identifies only protein the of shape on the Based • Bound Ligand Volume • • bound ligand around region Identifies protein in ligand abound of presence Requires Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Site Search Approaches Search Site • Use experimental Use data • • • Compare target to similar proteins similar to target Compare Site references from site binding Identified directed mutagenesis studies mutagenesis -directed Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Demo • • • • • structure to binding site Dock Remove in- Define BindingSite Prepare Ligand Prepare Protein Fubinaca) computational situ Ligand (MDMBsitu Ligand - – MDMB 6N4B MDMB - Fubinaca - Fubinaca - MDMB PDB Code: F - Fubinaca 6N4B N N Copyright©2019 Copyright©2019 O N GGA GGA Corp., All reserved. rights O O 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking WorkflowDocking Protein & LigandsProtein & Validate Results Preparation Docking Scoring • • • Docking tools in DS in tools Docking pose Find a conformations Generate • • • • • • Flexible Docking Flexible Pharmacophore Docking LigandsDock (LigandFit) Ligandslicense)Dockneed extra (GOLD, LigandsDock (LibDock) (CDOCKER) Ligands Dock Docking Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking from Tool from Docking Panel • Docking tools in in DS tools Docking • • • Dock Ligands (GOLD)Ligands Dock (LibDock) Ligands Dock (CDOCKER) Ligands Dock • Docking tools in DS (Protocol) DS in tools Docking • • • in DS2018) in Flexible Docking Flexible Docking Pharmacophore ( Ligands Dock ) LigandFit Copyright©2019 Copyright©2019 (Legacy GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | 3 GHz 3 Chem., 50(4), 726 - 1. Hartshorn, Med.et al. J. CDOCER LibDock Method on of performance Comparative get accurate docked poses in getdocked posesin accurateseconds AstexDiverse LibDock 741 (2007) 94 91 Accurately (Best) % Docked is optimized for speed: for optimized is and RMSD to X - get significant improvementin rank CDOCKER optimized for accuracy: is dataset 79 50 Accurately(Top) % Docked ray structure ray structure 0.8 1.2 (Best) AverageRMSD LibDock - orderingcorrect ofpose and CDOCKER CDOCKER and 1.5 3.8 (Top) AverageRMSD Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 5.0 0.5 Tim(min) 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | CDOCKER (HighTemperature Molecular Dynamics) Grid Generate Ligand Conformations Random (Rigid Random Output RefinedOutput Ligand Poses - Based Simulated AnnealingBased Full Minimization Full - Body) Rotation • • CDOCKER CDOCKER - grid of analysis Wu G, Robertson DH, Brooks CL III, III, CL Brooks DH, Robertson G, Wu , 13, 1549 13, 2003, Chem. Comp. (MD) methods (MD) byobtained Dynamic Molecular are conformations Ligand method. docking molecules a grid is CDOCK - A CHARMm based molecular docking: A case study of of study case A docking: molecular based - based MD docking MDbased docking algorithm. based -based Copyright©2019 Copyright©2019 Vieth GGA GGA Corp., All reserved. rights M. Detailed J. J. 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | The conformation generated bygenerated conformation The CDOCKER : Ligand Fitting Ligand : CDOCKER high temperature MD temperature high Site sphere Site Ligand Sphere centerSphere Ligand center Ligand Annealing Simulated Copyright©2019 Copyright©2019 Optimized Ligand Ligand Optimized GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Small Molecule Docking using CDOCKER using Docking Molecule Small • • a. Erickson a. Erickson et al. J Med Chem (2004) 47:45- Discovery Studio Grid PDB the 41 protein - • • • • accuracy on compromise significant No method Faster published in used representation -atom All ligands of set diverse Structurally - based approach used in used approach based ligand complexesligand from work a 55 (Success is defined as RMSD < 2Å from from X 2Å < RMSD as defined is (Success algorithm each for run docking best Single Successeachtimes algorithm ratesand CPU for Copyright©2019 Copyright©2019 - ray structure) GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking WorkflowDocking Protein & LigandsProtein & Validate Results Preparation Docking Scoring • • • • • Binding energycalculationmethodfollowing the based formula on Scoring functions databases based on statistical observations of intermolecular close contacts in large 3D binding partners interactions variousof countingtypes betweentwonumberbased of on the the AlsoknownEmpirical/Knowledge as • • • • • Ludi Jain Potential of Mean Force (PMF)& PMF04 Piecewise2 & Linear Potential1 (PLP) LigScore 1, 2 , & 3 & , 2 1, 1 & 2 & 1 E binding Literature ScoringFunctions Energy = E complex - - Based Functions based scoringfunctions – ( E ligand + E receptor ) Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Scoring • • • • Use consensus scoring scoring consensus Use complex scoring correctlyfunction every proteincan single rank - No Aim of scoring: major challenge a still is docked poses Scoring of • • • • between structural families structural between may vary interactions -ligand different protein of contribution Relative affinities binding their to according complexes -ligand protein of Ranking value energy lowestby pose binding correct the of Identification Combination of several scoring functions scoring of several Combination Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights ligand 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Types Functions Scoring of • • • Knowledge fieldForce - scoringEmpirical functions • • • • • Based on atomBased pair potentials derived from structural databases contributions entropy and solvation Could include (non- Handle the ligand binding prediction withthe useof potential energies affinity data Derived from training proteinsets- of toa score get for their binding affinities Forces and potentialsare collected from knownprotein- bonded interaction terms)bonded - derived functions based functions based ligand complexesdetermined withligand ligand complexes ligand Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Scoring Ligand Poses Protocol Poses Ligand Scoring • • • • Can also be applied during also be appliedCan docking be combinedCan Consensus in Scoring protocol Varityavailable functionsscoring of Used for finalevaluation docked of poses • • • • • Ludi PMF/PMF04 Jain PLP1/PLP2 LigScore1/LigScore2 Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking WorkflowDocking Protein & LigandsProtein & Validate Results Preparation Docking Scoring • • • • diagram) View non the View non the energy binding Calculate experimental results Compare with • • • Salt bridge RMSD with the reference structure Key residues bond interactions between ligand and receptor (2D receptor and ligand between interactions -bond -bond interactions receptor between and ligand Search and filter for the hits the for filter Search and Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Binding Energies Binding • Implicitsolvationused: be model can • • • • Implicit Distance Implicit Poisson Boltzmannnon- with Generalized Born with aSimple Switching(GBSW) Generalized Born with Molecular Volume(GBMV) ImplicitGeneralized Born E binding - Dependent Dielectrics Dependent = E Binding energy Binding complex polar Surface Area polar Copyright©2019 Copyright©2019 – (E ligand GGA GGA Corp., All reserved. rights + E receptor (PBSA) ) 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Analysis - Analyze Ligand Poses Ligand Analyze Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Non • • • • • Hydrophobic effects Van der π Electrostatic interactions Hydrogen bond interactions - - effects - (Non covalent waals forces bond) interactions interactions bond) Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | bonds C=O bond bond C=C C C C Type ‐ ‐ ‐ H bond H bond C O bond Covalent bond strenghts 165 kcal/ 143 kcal/ 103 kcal/ 86 kcal/ 81 kcal/ Energy mol mol mol mol mol Hydrophobic Type Hydrogen bond Electrostatic stacking π‐ VanWaals der π aromatic Non -Covalent bond Non ‐ <10 kcal/ Energy 2‐ 1‐ 0‐ 0.1 covalent interactions 30 kcal/ 20 kcal/ 10 kcal/ ‐ 1 kcal/ Copyright©2019 Copyright©2019 mol mol mol mol mol GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Analysis - Non • • Favorable ( - • • • • • • Bond Interactions Halogen Charge Halogen Halogen Br,(Cl, I) Halogen (Fluorine) Pi Pi Salt Bridge Attractive Charges - - Anion Cation See below See ) •Donor •Acceptor •Charge Repulsion Bumps •Steric • • • • • • • • • • • • Other Hydrophobic Pi Sulfur Pi Metal Pi Pi Alkyl Amide Pi Pi ------Lone Pair Sulfur Alkyl Sigma T Pi Pi Stacked Donor clashes Unfavorable - - - Acceptor clashes clashes Acceptor Acceptor Acceptor - - X Pi Stacked Shaped • • • • • • • Hydrogen Bond Salt Bridge Water HydrogenBond Bond WaterHydrogen Mediated DonorPi Hydrogen Bond Carbon HydrogenBond Conventional HydrogenBond •Charged atoms •Hydrogenbond acceptor •Hydrogenbond donor Copyright©2019 Copyright©2019 Unsatisfied Unsatisfied GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Pose Analysis • • • • Fits saved to a molecule molecule table a savedtoFits Optional energyminimization of eachpose protocol Poses Ligand AnalyzeRun Plot Charts of Scoring • • • • • • • • Ligand MinimizationProtocol Heat Maps Contacts Hbonds Hit RatePlot Histogram SimpleLine Plot Can be exportedCan to an SDfile Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Hands on • • • protocol Pose Find the poses which interact which poses withthe Find Draw the heat mapChart by tools Analyze • • scheme and3D 2D interaction diagram Generate W279 M363, and calculate binding energies energies calculate bindingand FUB FUB poses by Analyze Ligand by Analyze poses Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Docking WorkflowDocking Protein & LigandsProtein & Validate Results Preparation Docking Scoring T hroughput Repeat Cycle= V irtual irtual ( vHTS S H creening igh igh ) • • Requirements very important. is steps each in phase evaluation the success, of therate maximize to In order • • • • proceeding the docking and scoring steps steps scoring and docking the proceeding before library in molecules the Prioritized technique docking parameters the of Optimize molecules Bound compounds active Known decoy and Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | Q&A Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights 172 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | 3DS.COM/BIOVIA © Dassault Systèmes | Confidential Information | 3/16/2019 | For more informationplease contact… Ph : (02) 2795 1777 2795 (02) : 台北市114 msc - 內湖區新湖一路36 中華民國 www.gga.asia [email protected] x 3014 Fax:x (02) 2793 8009 台灣巷28 號 Copyright©2019 Copyright©2019 GGA GGA Corp., All reserved. rights