DOCSLIB.ORG

Assessment of the Efficacy of New Derivatives of Trazodone As Antidepressants: a Computational Approach

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Assessment of the Efficacy of New Derivatives of Trazodone As Antidepressants: a Computational Approach The University of Dodoma University of Dodoma Institutional Repository http://repository.udom.ac.tz Natural Sciences Master Dissertations 2020 Assessment of the efficacy of new derivatives of trazodone as antidepressants: A computational approach Abdul, Anifa Hassan The University of Dodoma Abdul, A. H. (2020). Assessment of the efficacy of new derivatives of trazodone as antidepressants: A computational approach (Master's Dissertation). The University of Dodoma, Dodoma. http://hdl.handle.net/20.500.12661/2674 Downloaded from UDOM Institutional Repository at The University of Dodoma, an open access institutional repository. ASSESSMENT OF THE EFFICACY OF NEW DERIVATIVES OF TRAZODONE AS ANTIDEPRESSANTS: A COMPUTATIONAL APPROACH ANIFA HASSAN ABDUL MASTER OF SCIENCE IN CHEMISTRY THE UNIVERSITY OF DODOMA DECEMBER, 2020 ASSESSMENT OF THE EFFICACY OF NEW DERIVATIVES OF TRAZODONE AS ANTIDEPRESSANTS: A COMPUTATIONAL APPROACH BY ANIFA HASSAN ABDUL HOLDER OF BACHELOR OF SCIENCE IN CHEMISTRY, UNIVERSITY OF BAGAMOYO A DISSERTATION SUBMITTED FOR THE PARTIAL FULFILL- MENT OF THE REQUIREMENT FOR THE DEGREE MASTER OF SCIENCE IN CHEMISTRY THE UNIVERSITY OF DODOMA DECEMBER, 2020 DECLARATION AND COPYRIGHT I, Anifa Hassan Abdul, declare that this dissertation is my original work and that it has not been presented to any other University for a similar or any other degree award. Signature: Date: 6th December 2020 No part of this dissertation may be reproduced, stored in any retrieval system, or transmitted in any form or by any means without prior written permission of the au- thor or the University of Dodoma. If transformed for publication in any other format shall be acknowledged that “this work has been submitted for degree award at the University of Dodoma”. i CERTIFICATION “The undersigned certifies that they have read and hereby recommends for the acceptance by the University of Dodoma a dissertation entitled “Assessment of the efficacy of new derivatives of trazodone as antidepressants: A computational ap- proach” in partial fulfillment of requirements for the degree of Master of Science in Chemistry of the University of Dodoma. Prof. Numbury Surendra Babu (SUPERVISOR) Signature: ____________________ Date: 6th December 2020 Dr. Abdo A Elfiky (SUPERVISOR) Signature Date: 6th December 2020 ii ACKNOWLEDGEMENT My extreme praises throughout my research work go to the Almighty omnipotent Allah for his merciful blessings, compassion, and guidance bestowed upon me. My most profound sense of gratitude goes to my supervisors Prof. Numbury Surendra Babu and Dr. Abdo Elfiky, for providing me with fruitful guidance, comments, and full support throughout my research work. It has been a great honor and privilege to study under their guidance. I am extending my genuine gratitude to the Department of Chemistry at the University of Dodoma and the Department of Biophysics at Cairo University for their support in my research work. Indeed, no words can express my humbleness grateful- ness sincere to all staff at the College of Natural and mathematical science especially Prof Said Vuai, Dr. Sahini Mtabazi, Dr. Andrew Banyikwa, and Mr. Katundu Saidi for their supportive ideas and immense knowledge, furthermore to my colleague MSc. Chemistry students for their support during my studies. No attempt in life can be satisfactorily completed without the guidance and support of parents, siblings, relatives, and friends. So finally, my most resounding heartfelt acknowledgment goes to my mother, sisters, brothers, and our last-born Ai- sha for the love, comfort, guidance, support, and prayers that kept me going ahead straight and smiling. Additionally, my heartfelt sincere thanks go to Mr. Frank Beichumila, Mr. Ngeleja Hamisi, Madam Fatuma Mressa, and Madam Maisha Sabimana for their encouragement, enthusiasm, and comfort throughout my studying life at UDOM. Also, thanks to my all-time friends for lending me a shoulder to lean on. iii DEDICATION I dedicate this work to my late father, Mr. Abdul Hassan, may his soul rest in peace in addition to that, to the apple of my eyes, my lovely mother Zamda Mohammed, My uncle Almadan Amani and my brother Seif .S. Sareva. iv ABSTRACT Depression has been the number one disease, causing a high motility rate in the world, marking the need for new highly effective antidepressants that can alleviate the situation. Unfortunately, the price of carrying out experimentally the whole process of drug discovery and design costs an endeavor billion of money. Yet, computer-aided drug design is a cost-effective way of obtaining new potential drugs within a short period of time. A study helpful in designing potent drug candidate as an antidepressant with increased efficacy was carried out. The Density Functional Theory (DFT) method with B3LYP 6-311G++(d,p) basis set were employed using Gaussian 09 software to find the minimum energy configuration of the studied molecules (new derivatives of trazodone). Afterward, a molecular docking simulation of the studied molecules within the ligand pocket of the Human serotonin transporter as an antidepressant tar- get followed. The molecular docking simulation was done using AutoDock Vina 1.1.2 software together with AutoDock tool 1.5.6 and PyMOL 1.7.4.5 software for the preparation of the docking molecules and the analysis of the results, respectively. From the analyzed molecular docking simulation results, it was demonstrated that all the proposed trazodone derivatives were revealed to be potential drug candi- dates with enhanced efficacy than the parent trazodone drug except for derivative ligand T2. Despite that from the analyzed DFT calculation results, the lig- and T5, T7, T8, and T10 expressed significant chemical reactivity and thermodynamic properties in comparison with the trazodone. A further study on these derivatives as the potent antidepressant candidate is recommended. v TABLE OF CONTENTS DECLARATION AND COPYRIGHT ......................................................................... i CERTIFICATION ....................................................................................................... ii ACKNOWLEDGEMENT .......................................................................................... iii DEDICATION ............................................................................................................ iv ABSTRACT ................................................................................................................. v TABLE OF CONTENTS ............................................................................................ vi LIST OF TABLES .................................................................................................... viii LIST OF FIGURES .................................................................................................... ix LIST OF ABBREVIATIONS .................................................................................... xii CHAPTER ONE ........................................................................................................ 1 1.0 INTRODUCTION ................................................................................................. 1 1.1 General Introduction .............................................................................................. 1 1.1.1 Trazodone ............................................................................................................ 2 1.1.2 Molecular Modeling ............................................................................................ 4 1.1.3 Computer-aided drug design ............................................................................... 6 1.2 Statement of the Problem ....................................................................................... 7 1.3 Objectives ............................................................................................................... 8 1.3.1 General Objective................................................................................................ 8 1.3.2 Specific Objectives.............................................................................................. 8 1.4 Hypothesis .............................................................................................................. 8 1.5 Significance of the Study ....................................................................................... 9 CHAPTER TWO ..................................................................................................... 10 2.0 LITERATURE REVIEW .................................................................................... 10 2.1 Human serotonin transporter ................................................................................ 10 2.2 Interaction of high efficacious antidepressants with the human serotonin transporter’s ligand pocket. ................................................................................. 13 2.2.1 Interaction of human serotonin transporter with S-citalopram ......................... 13 2.2.2 Interaction of human serotonin transporter with fluvoxamine .......................... 17 2.3 Mechanism of action of trazodone in overcoming major depression disorders... 20 vi 2.4 Drugs structure and activity relationship ............................................................. 21 2.5 Density Functional Theory ................................................................................... 22 2.6 Molecular docking studies ................................................................................... 23 CHAPTER
Load more

Recommended publications
  • Identifying of Selective Agonists Targeting Lxrβ from Terpene Compounds of Alismatis Rhizoma
    Identifying of selective agonists targeting LXRβ from terpene compounds of Alismatis Rhizoma Chuanjiong Lin Sichuan University Jianzong Li ( [email protected] ) Sichuan University Chuanfang Wu Sichuan University Jinku Bao Sichuan University Original paper Keywords: Hyperlipidemia, LXRα, LXRβ, molecular docking, molecular dynamics simulations, agonist, Alismatis Rhizoma Posted Date: February 1st, 2021 DOI: https://doi.org/10.21203/rs.3.rs-164666/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published at Journal of Molecular Modeling on February 22nd, 2021. See the published version at https://doi.org/10.1007/s00894-021-04699-z. Page 1/40 Abstract Hyperlipidemia is thought as an important contributor to coronary disease, diabetes and fatty liver. Liver X receptors β (LXRβ) was considered as a validated target for hyperlipidemia therapy due to its role in regulating cholesterol homeostasis and immunity. However, many current drugs applied in clinic are not selectively targeting LXRβ and they can also activate LXRα which activate SREBP-1c worked as activator of lipogenic genes. Therefore, exploiting agonists selectively targeting LXRβ are urgent. Here, computational tools were used to screen potential agonists selectively targeting LXRβ from 112 terpenes of Alismatis Rhizoma. Firstly, structural analysis between selective and nonselective agonists were used to explore key residues of selective binding with LXRβ. Our data indicated that Phe271, Ser278, Met312, His435, Trp457 were important to compounds binding with LXRβ, suggesting that engaging ligand interaction with these residues may provide directions for development of ligands with improved selective proles.
    [Show full text]
  • Metalloboranes from First-Principles Calculations: a Candidate for High-Density Hydrogen Storage
    Metalloboranes from first-principles calculations: A candidate for high-density hydrogen storage A. R. Akbarzadeh, D. Vrinceanu, and C.J. Tymczak Department of Physics, Texas Southern University, Houston, Texas 77004, USA Abstract Using first principles calculations, we show the high hydrogen storage capacity of a new class of compounds, metalloboranes. Metalloboranes are transition metal (TM) and borane compounds that obey a novel-bonding scheme. We have found that the transition metal atoms can bind up to 10 H2-molecules with an average binding energy of 30 kJ/mole of H2, which lies favorably within the reversible adsorption range. Among the first row TM atoms, Sc and Ti are found to be the optimum in maximizing the H2 storage on the metalloborane cluster. Additionally, being ionically bonded to the borane molecule, the TMs do not suffer from the aggregation problem, which has been the biggest hurdle for the success of TM- decorated graphitic materials for hydrogen storage. Furthermore, since the borane 6-atom ring has identical bonding properties as carbon rings it is possible to link the metalloboranes into metal organic frameworks (MOF’s), which are thus able to adsorb hydrogen via Kubas interaction as well as the well-known van der Waals interaction. Finally, we construct a simple Monte-Catlo algorithm for Hydrogen uptake and show that Titanium metalloboranes in a MOF5 structure can absorb up to 11.5% hydrogen per weight at 100 bar of pressure. I. Introduction Due to the geographical distribution and supply limitation of fossil fuel resources and the increasing perceived negative impact of carbon dioxide emission in the environment, it is advantageous for the societies to take action in the search and implementation of alternative energy systems.
    [Show full text]
  • Synthesis and a Combined Simil
    Er et al. Chemistry Central Journal (2018) 12:121 https://doi.org/10.1186/s13065-018-0485-3 Chemistry Central Journal RESEARCH ARTICLE Open Access An integrated approach towards the development of novel antifungal agents containing thiadiazole: synthesis and a combined similarity search, homology modelling, molecular dynamics and molecular docking study Mustafa Er1*, Abdulati Miftah Abounakhla1, Hakan Tahtaci1, Ali Hasin Bawah1, Süleyman Selim Çınaroğlu2, Abdurrahman Onaran3 and Abdulilah Ece4* Abstract Background: This study aims to synthesise and characterise novel compounds containing 2-amino-1,3,4-thiadiazole and their acyl derivatives and to investigate antifungal activities. Similarity search, molecular dynamics and molecular docking were also studied to fnd out a potential target and enlighten the inhibition mechanism. Results: As a frst step, 2-amino-1,3,4-thiadiazole derivatives (compounds 3 and 4) were synthesised with high yields (81 and 84%). The target compounds (6a–n and 7a–n) were then synthesised with moderate to high yields (56–87%) by reacting 3 and 4 with various acyl chloride derivatives (5a–n). The synthesized compounds were characterized using the IR, 1H-NMR, 13C-NMR, Mass, X-ray (compound 7n) and elemental analysis techniques. Later, the in vitro anti- fungal activities of the synthesised compounds were determined. The inhibition zones exhibited by the compounds against the tested fungi, their minimum fungicidal activities, minimum inhibitory concentration and the lethal dose values ­(LD50) were determined. The compounds exhibited moderate to high levels of activity against all tested pathogens. Finally, in silico modelling was used to enlighten inhibition mechanism using ligand and structure-based methods.
    [Show full text]
  • Presidential Search Committee Meets, Reviews Upcoming Work
    ETHEMedford, MA 02155 TUFTSTuesday, November 26,1991 DAILYJVol XXIII, Number 58 Faculty tables vote on Presidential search committee World Civ proposal meets, reviews upcoming work courses iUC to be intcrdiscipli by SCHAEF1cR nary. intcgr;ltblg disciplines fr()n by MAUREEN LENIHAN Senior Staff Writer Daily Editorial Board and PATRICK HEALY at leiist three of the five distribu The 19-member search com- Dally Edil(~r1alhtUd tion areas. mittee fonned to begin the pro- Although the proposed World Since 1986. threeteamsoffac cess of selecting anew university CivilizationsFoundation rcquire- ult y. including one professor frorr president met for the first time inent was briefly presented at the the School ofEngineering,devel yesterday, familiariz,ing them- Liberal Arts and Jackson facully oped three two-semester course: selves with their task and the meeting yesterday. the LAM fac- which were ultiinately opened tc committee‘s initial duties includ- ulty postponed further discussion students to take on a voluntce ing formali~inga Job description and voting on the prognun until basis. These courses, titled “P for the post. Dec. 11. Sense of Place.” “Time and Cal The committee. representing Dean of College of Liberal endars,“and “Memory and Iden trustees. administrators, faculty Arts and Jackson Mary Ella tity.“wereestablishedwith fincan members. staff members. stu- Fcinleibmoved tocrcate the Dec. cia1 support from ihe Davis Foun dents. and alumni, was fonncd in 1 I meeting since other meeting dation. the National Endowmen response toai miouiiccmcnt last topics preceding the World Civ for the Humimities, and the Uni May that University president presentation took up most of the versit y.
    [Show full text]
  • Design, Synthesis and Evaluation of Bitopic Arylpiperazine-Phthalimides As Selective Dopamine D3 Receptor Agonists
    Electronic Supplementary Material (ESI) for MedChemComm. This journal is © The Royal Society of Chemistry 2018 Design, Synthesis and Evaluation of Bitopic Arylpiperazine-phthalimides as Selective Dopamine D3 Receptor Agonists Yongkai Caoa,b,c,1, Ningning Sunb,1, Jiumei Zhangc,1, Zhiguo Liud, Yi-zhe Tangc, Zhengzhi Wuc,*, Kyeong-Man Kimb,* and Seung Hoon Cheonb, a Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China b College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea c The First Affiliated Hospital of Shenzhen University, Shenzhen 518035,China d Chemical Biology Research at School of Pharmaceutical sciences, Wenzhou Medical University, Wenzhou 325035, China 1. Docking The SYBYL-X 2.0 program was used for ligand sketching, hydrogen addition, and minimization with the Trips force field and Gasteriger-Huckel charges.1 The dopaminergic receptors, D3R (PDB code: 3PBL) and D2R (PDB code: 6C38), were refined using the Biopolymer module implemented in SYBYL-X 2.0. After the removal of all the ligands and water molecules, the N- and C-termini were treated with charges. Subsequently, hydrogens were added and staged minimizations were performed using AMBER7_FF99 force field and Gasteriger-Marsili charges. The most selective D3R ligand among the identified compounds, compound 9i, was docked into the refined D2R 2 and D3R with the program LeDock (www.lephar.com). Briefly, a rectangular box was generated in the LeDockGUI, a free graphics user interface of VMD, based on the binding pockets of eticlopride in D3R and risperidone in D2R. The compound 9i was docked into the dopaminergic receptors using LeDock program and for each ligands, 30 poses were generated and clustered by a RMSD cutoff of 1 Å.
    [Show full text]
  • Molecular Docking : Current Advances and Challenges
    ARTÍCULO DE REVISIÓN © 2018 Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Zaragoza. This is an Open Access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). TIP Revista Especializada en Ciencias Químico-Biológicas, 21(Supl. 1): 65-87, 2018. DOI: 10.22201/fesz.23958723e.2018.0.143 MOLECULAR DOCKING: CURRENT ADVANCES AND CHALLENGES Fernando D. Prieto-Martínez,1a Marcelino Arciniega2 and José L. Medina-Franco1b 1Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Avenida Universidad # 3000, Delegación Coyoacán, Ciudad de México 04510, México 2Instituto de Fisiología Celular, Departamento de Bioquímica y Biología Estructural, Universidad Nacional Autónoma de México E-mails: [email protected], [email protected],[email protected] ABSTRACT Automated molecular docking aims at predicting the possible interactions between two molecules. This method has proven useful in medicinal chemistry and drug discovery providing atomistic insights into molecular recognition. Over the last 20 years methods for molecular docking have been improved, yielding accurate results on pose prediction. Nonetheless, several aspects of molecular docking need revision due to changes in the paradigm of drug discovery. In the present article, we review the principles, techniques, and algorithms for docking with emphasis on protein-ligand docking for drug discovery. We also discuss current approaches to address major challenges of docking. Key Words: chemoinformatics, computer-aided drug design, drug discovery, structure-activity relationships. Acoplamiento Molecular: Avances Recientes y Retos RESUMEN El acoplamiento molecular automatizado tiene como objetivo proponer un modelo de unión entre dos moléculas. Este método ha sido útil en química farmacéutica y en el descubrimiento de nuevos fármacos por medio del entendimiento de las fuerzas de interacción involucradas en el reconocimiento molecular.
    [Show full text]
  • O (N) Methods in Electronic Structure Calculations
    O(N) Methods in electronic structure calculations D R Bowler1;2;3 and T Miyazaki4 1London Centre for Nanotechnology, UCL, 17-19 Gordon St, London WC1H 0AH, UK 2Department of Physics & Astronomy, UCL, Gower St, London WC1E 6BT, UK 3Thomas Young Centre, UCL, Gower St, London WC1E 6BT, UK 4National Institute for Materials Science, 1-2-1 Sengen, Tsukuba, Ibaraki 305-0047, JAPAN E-mail: [email protected] E-mail: [email protected] Abstract. Linear scaling methods, or O(N) methods, have computational and memory requirements which scale linearly with the number of atoms in the system, N, in contrast to standard approaches which scale with the cube of the number of atoms. These methods, which rely on the short-ranged nature of electronic structure, will allow accurate, ab initio simulations of systems of unprecedented size. The theory behind the locality of electronic structure is described and related to physical properties of systems to be modelled, along with a survey of recent developments in real-space methods which are important for efficient use of high performance computers. The linear scaling methods proposed to date can be divided into seven different areas, and the applicability, efficiency and advantages of the methods proposed in these areas is then discussed. The applications of linear scaling methods, as well as the implementations available as computer programs, are considered. Finally, the prospects for and the challenges facing linear scaling methods are discussed. Submitted to: Rep. Prog. Phys. arXiv:1108.5976v5 [cond-mat.mtrl-sci] 3 Nov 2011 O(N) Methods 2 1.
    [Show full text]
  • Use of QSAR Global Models and Molecular Docking for Developing New
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 25 October 2019 Use of QSAR global models and molecular docking for developing new inhibitors of c-src tyrosine kinase Robert Ancuceanu1, Bogdan Tamba*2, Cristina Silvia Stoicescu3, Mihaela Dinu1 1Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 2Advanced Research and Development Center for Experimental Medicine (CEMEX), Grigore T. Popa University of Medicine and Pharmacy of Iasi, Romania ([email protected]); 3Institute of Physical Chemistry "Ilie Murgulescu", Bucharest, Romania Abstract Prototype of a family of at least nine members, c-src tyrosine kinase is a therapeutically interesting target, because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We have explored the use of global QSAR models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a data set of 1038 compounds from ChEMBL and 19 blocks of molecular descriptors, we have developed over 200 QSAR classification models, based on six machine learning algorithms and 17 feature selection methods. We have selected 49 with reasonably good performance (positive predictive value and balanced accuracy higher than 70% in nested cross validation) and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over the “named” ZINC data set (over 100,000 compounds).
    [Show full text]
  • Curriculum Vitae
    CURRICULUM VITAE Christopher J. Tymczak Tenured Associate Professor Director Department of Physics Texas Southern University High Texas Southern University Performance Computing Center Houston, Texas 77004 Texas Southern University Office: (713) 313-1849 Houston, Texas 77004 Email: [email protected] (http://hpcc.tsu.edu/) (http://physics.tsu.edu/) Co-Director Visiting Research Scientist NSF CREST Center for Research on Group T-1 Complex Networks Los Alamos National Laboratory Texas Southern University Los Alamos, New Mexico, 87507 Houston, Texas 77004 I specialize in the identification, development, and implementation of new scientific codes for exploiting advanced computing resources impacting large scale computation in diverse areas in Many-body physics, Quantum Chemistry and ab initio Molecular Dynamics. I am a tenured associate professor of physics at Texas Southern University, where I am spearheading the integration of supercomputing resources into various STEM programs. I am also the founder and director of the Texas Southern High Performance Computing Center (TSU-HPCC). At Los Alamos National Laboratory, I am a permanent scientific associate within the FreeON initiative, involving the development of massively parallel linear scaling quantum chemistry methods, currently under development in collaboration with Dr. Matt Challacombe (T-12) and Dr. Anders Niklasson (T-1). I was one of the first to exploit wavelet-based methods in large scale computing for understanding the electronic structure of materials. For the last six years, I have advanced the FreeON development through the exploitation of advanced data structures and advanced machine architectures. FreeON is now recognized as one of the first quantum chemical codes with demonstrable scalable parallelism within large- scale parallel clusters.
    [Show full text]
  • Lawrence Berkeley National Laboratory Recent Work
    Lawrence Berkeley National Laboratory Recent Work Title From NWChem to NWChemEx: Evolving with the Computational Chemistry Landscape. Permalink https://escholarship.org/uc/item/4sm897jh Journal Chemical reviews, 121(8) ISSN 0009-2665 Authors Kowalski, Karol Bair, Raymond Bauman, Nicholas P et al. Publication Date 2021-04-01 DOI 10.1021/acs.chemrev.0c00998 Peer reviewed eScholarship.org Powered by the California Digital Library University of California From NWChem to NWChemEx: Evolving with the computational chemistry landscape Karol Kowalski,y Raymond Bair,z Nicholas P. Bauman,y Jeffery S. Boschen,{ Eric J. Bylaska,y Jeff Daily,y Wibe A. de Jong,x Thom Dunning, Jr,y Niranjan Govind,y Robert J. Harrison,k Murat Keçeli,z Kristopher Keipert,? Sriram Krishnamoorthy,y Suraj Kumar,y Erdal Mutlu,y Bruce Palmer,y Ajay Panyala,y Bo Peng,y Ryan M. Richard,{ T. P. Straatsma,# Peter Sushko,y Edward F. Valeev,@ Marat Valiev,y Hubertus J. J. van Dam,4 Jonathan M. Waldrop,{ David B. Williams-Young,x Chao Yang,x Marcin Zalewski,y and Theresa L. Windus*,r yPacific Northwest National Laboratory, Richland, WA 99352 zArgonne National Laboratory, Lemont, IL 60439 {Ames Laboratory, Ames, IA 50011 xLawrence Berkeley National Laboratory, Berkeley, 94720 kInstitute for Advanced Computational Science, Stony Brook University, Stony Brook, NY 11794 ?NVIDIA Inc, previously Argonne National Laboratory, Lemont, IL 60439 #National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, TN 37831-6373 @Department of Chemistry, Virginia Tech, Blacksburg, VA 24061 4Brookhaven National Laboratory, Upton, NY 11973 rDepartment of Chemistry, Iowa State University and Ames Laboratory, Ames, IA 50011 E-mail: [email protected] 1 Abstract Since the advent of the first computers, chemists have been at the forefront of using computers to understand and solve complex chemical problems.
    [Show full text]
  • Computer?Aided Docking: an Invaluable Tool in Drug Discovery
    IJPCBS 2017, 7(4), 453-458 Nagaraju Pappula et al. ISSN: 2249-9504 INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES Available online at www.ijpcbs.com Review Article COMPUTER‐AIDED DOCKING: AN INVALUABLE TOOL IN DRUG DISCOVERY AND MOLECULAR BIOLOGY Nagaraju Pappula*, Ravichandra Sharabu and Pradeep Kumar Thadiboina Hindu College of Pharmacy, Amaravathi Road, Guntur – 522 002, Andhra Pradesh, India. ABSTRACT Docking is a pharmacologically important tool in the field of drugs designing and computational biology. It works with the basic understanding of structure prediction of intermolecular complex formed between drug and its target molecule. The aim of ligand-receptor docking is to identify the pivotal active binding sites of a ligand with a protein of already known three-dimensional structures. Molecular docking is a computational procedure that aims to predict the favored orientation of a ligand to its macromolecular target when these are bound to each other to form a stable complex. The present review focused on importance of docking and its applications in drug innovation. The relevant basic theories including sampling algorithms, scoring functions are summarized. The differences in and performances of available docking software are also discussed. Keywords: Dock, Drug discovery, Scoring and Lipinski rule. INTRODUCTION coordinates. Furthermore, for flexible ligand Computational docking or computer‐aided docking, we should also define ligand bonds that docking is a tremendously valuable tool to gain are rotatable. All this will be done in a tool called an understanding of protein-ligand interactions Auto Dock Tools (ADT). which is important for the drug discovery 1-3. Docking server integrates a number of Procedure8,9 computational chemistry software specifically Step-1 aimed at correctly calculating parameters4 Receptor building – The receptor complex is needed at different steps of the docking downloaded from RCSB PDB.
    [Show full text]
  • Recent Advances in in Silico Target Fishing
    molecules Review Recent Advances in In Silico Target Fishing Salvatore Galati 1 , Miriana Di Stefano 1 , Elisa Martinelli 1, Giulio Poli 1,* and Tiziano Tuccinardi 1,2 1 Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; [email protected] (S.G.); [email protected] (M.D.S.); [email protected] (E.M.); [email protected] (T.T.) 2 Center for Biotechnology, Sbarro Institute for Cancer Research and Molecular Medicine, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA * Correspondence: [email protected]; Tel.: +39-0502219603 Abstract: In silico target fishing, whose aim is to identify possible protein targets for a query molecule, is an emerging approach used in drug discovery due its wide variety of applications. This strategy allows the clarification of mechanism of action and biological activities of compounds whose target is still unknown. Moreover, target fishing can be employed for the identification of off targets of drug candidates, thus recognizing and preventing their possible adverse effects. For these reasons, target fishing has increasingly become a key approach for polypharmacology, drug repurposing, and the identification of new drug targets. While experimental target fishing can be lengthy and difficult to implement, due to the plethora of interactions that may occur for a single small-molecule with different protein targets, an in silico approach can be quicker, less expensive, more efficient for specific protein structures, and thus easier to employ. Moreover, the possibility to use it in combination with docking and virtual screening studies, as well as the increasing number of web-based tools that have been recently developed, make target fishing a more appealing method for drug discovery.
    [Show full text]