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 : 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 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. procedure, i.e. accurate ligand geometry Step-2 optimization, energy minimization, charge After downloading the pdb format of the calculation, docking calculation and protein- protein, remove the water molecules the solvent ligand complex representation. Thus, the use of molecules and all non-interacting ions by editing docking server allows the user to carry out the TEXT of the protein. highly efficient and robust docking calculations5 Step-3 by integrating a number of admired software Add the missing hydrogens/side chain atoms used in in-silico chemistry into one and minimized the protein complex (AMBER comprehensive web service. Program). Step-4 PROCEDURE FOR DOCKING Clean the minimized complex (delete all the Preparing the protein and ligand for water and the solvent molecules and all non- docking6 interacting ions). Docking algorithms require each atom to have a Step-5 charge and an atom type that describes its Separate the active site of minimized complex in properties 7. However, the PDB (Protein Data macromolecule (LOCK) and ligand (KEY) and Base) structure lacks these. So, we have to prepare the docking suitable files for LOCK and prepare the protein and ligand files and to KEY (pdbqt files). include these values along with the atomic

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Step-6 stable adduct. Depending upon binding Prepare all the needing files for docking (grid properties of ligand and target, it predicts the parameter file, map files, docking parameter three-dimensional structure of any complex. At files including GA (Genetic Algorithm) present, docking technique is utilized to predict parameter likes Population size, Generations etc the tentative binding parameters of ligand- which are necessary for docking accuracy). Set receptor complex beforehand. Molecular the output path to store the prepared structure. docking generates different possible adduct Step-7 structures that are ranked and grouped together The predicted and later the ligand are uploaded. using scoring function in the software13. Arrange all the parameters such as number of Molecular docking of small molecules to a target pose to be obtained and score and run the includes a pre-defined sampling of possible Docking. conformation of ligand in the particular groove Step-8 of target in an order to establish the optimized The docking score is calculated and even the conformation of the complex. This can be made fitness is displayed, analyze your data and select possible using scoring function of software. the most optimum ligand and its pose. Since the infrared spectroscopy, X- Step-9 ray crystallography and Nuclear Magnetic The complex can be viewed and checked for the Resonance (NMR) spectroscopy are the orientation of the ligand with the receptor. techniques for the investigation and Step-10 establishment of three dimensional structures of To representation and analyzing of orientation any organic molecule/ bio-molecular targets14. of the ligand with the receptor viewed in various A new multi-objective strategy for molecular formats. docking, named as MoDock, is presented to Eg: Ball and stick view format further improve the docking accuracy with available scoring functions. Tests of MoDock PROTEIN DATA BANK (PDB) against the GOLD test data set reveal the multi- Research Collaborators for structural objective strategy improves the docking Bioinformatics Protein Data Bank (RCSB PDB) accuracy over the individual scoring functions. began in 1970's by group of the young Meanwhile, a 70% ratio of the good docking crystallographers, including Edgar Meyer, solutions with the RMSD (simply root-mean- Gerson Coheon and Helen M Berman7. The PDB square deviation) value below 1.0 Ao archive is maintained by the members of the outperforms other six commonly used docking worldwide PDB (wwPDB) – the RCSB (Research programs, even with a flexible receptor docking Co-laboratory for Structural Bioinformatics) program included 15. PDB, EBI-MSD (Electrically Macromolecular Structure Relational Database), PDBj (Protein GOLD Data Bank Japan) and the BMRB (British Market PARAMETERS IN DOCKING STUDIES Research Bureau Limited). Data deposited to the LIPINSKI five rule 16 archive is processed using agreed-upon  To evaluate drug likeness or determine if a standards for full validation of the data10. These chemical compound has properties that data are forwarded to the RCSB PDB for release would make it a likely orally active drug in into the archive. WwPDB (Worldwide protein humans derived. data bank) members also maintain websites that  Because of the realization, that HTS (high provide different views to the data. through put screening) is identifying large numbers of hit compounds and many of IMPORTANCE OF DOCKING IN NEW DRUG which did not possess ‘drug‐like’ properties. DEVELOPMENT  By Christopher Lipinski in 1997, most orally Ligand-protein docking is an optimization of administered drugs are relatively small and problem based on predicting the position of a moderately lipophilic (A molecular mass ligand with the lowest binding energy in the less than 500 Daltons). active site of the receptor. The net predicted  RO5 identifies molecular properties binding free energy (ΔGbind) is revealed in terms important for a drug's pharmacokinetics in of various parameters: Hydrogen bond (ΔGhbond), the human body: absorption, distribution, 11 electrostatic (ΔGelec), Torsional free energy metabolism, and excretion ("ADME"). 12 (ΔGtor), Dispersion and repulsion (ΔGvdw),  No more than 5 hydrogen bond donors Desolvation (ΔGdesolv), Total internal energy (the total number of nitrogen–hydrogen (ΔGtotal) and Unbound system’s energy (ΔGunb). and oxygen–hydrogen bonds). Molecular docking is a kind  Not more than 10 hydrogen bond of bioinformatic modeling which involves the acceptors (all nitrogen or oxygen interaction of two or more molecules to give the atoms).

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 An octanol‐water (O/W) partition students in proper selection of the drug and coefficient log P not greater than 5. knowing whether the drug is suitable for oral  However, the rule does not predict when a formulations22. For Medicinal chemistry pharmacologically active lead structure is students involved in drug designing, CADD optimized to increase the activity and (Computer Aided Drug Designing), selectivity. understanding this rule will help you a lot in designing suitable homologues of rugs and fine Other rules to define drug‐like properties tuning your drug with suitable modifications23.  Majority of compounds with good oral Comprehensively utilized docking tools employ bioavailability in rats had less than 10 search algorithms such as genetic algorithm, rotatable bonds (ROTB) and polar fragment-based algorithms, Monte Carlo surface area (PSA) less than 140 Å2 17. algorithms24 and  Compounds with log P less than three algorithms. Besides this, and PSA greater than 75 Å2 were six there are some tools 10 such as DOCK, GOLD, times less likely to exhibit adverse Flex-X and ICM which are mainly used for high events in in‐vivo tolerance studies 18. throughput docking simulations. There are  Number of aromatic rings greater than various kinds of molecular docking procedures three significantly increases the risk of involving either ligand/target flexible or rigid compound attrition 19. based upon the objectives of docking  "Flatness" of compounds as defined by simulations like flexible ligand docking (target the fraction of carbons that are SP3 as rigid molecule), rigid body docking (both the hybridized, guarantees a success in target and ligand as rigid molecules) and flexible clinical development 20. docking (both interacting molecules as  Used as application in design of drug flexible)25. On the basis of the results for the top and treatment in major diseases and scored poses, the performance of the academic including cancer 21. programs conform to the following order26: LeDock (57.4%) > rDock (50.3%) ∼ Auto Dock How this rule benefits? Vina (49.0%) > Auto Dock (PSO) (47.3%) > UCSF The rule describes molecular properties DOCK (44.0%) > Auto Dock (LGA) (37.4%), and important for a drug’s pharmacokinetics in the that of the commercial programs confirm to the human body, including their absorption, following order: GOLD (59.8%) > Glide (XP) distribution, metabolism, and excretion (57.8%) > Glide (SP) (53.8%) > Surflex-Dock (“ADME”). However, the rule does not predict if (53.2%) > Ligand Fit (46.1%) > MOE-Dock a compound is pharmacologically active. This (45.6%). rule helps Pharmaceutics/Industrial Pharmacy

Fig. 1: Flow Chart

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IS AN ACCURATE? IF YES HOW CAN I structures below 2.2 Å. All the same, care should CONSIDER IN INVOLVING RESEARCH? be taken while picking a structure. Molecular docking is an invaluable tool the field The scoring functions used in docking, almost all of molecular biology, computational structural of them, do not take into account the role played biology, computer aided drug designing and by covalently bound inhibitors or ions 35. pharmacogenomics 27. It is an important The methodology and research in protein– common component of the drug discovery protein docking have to be greatly increased as toolbox and its relative low-cost implications the success in this field is greatly hampered by and perceived simplicity of use has stimulated many false positives and false negatives 36. an ever increasing popularity within academic communities 28. Molecular docking is a study of DISCUSSION how two or more molecular structures, for Each docking program operates slightly instance, drug and catalyst or macromolecule differently; they share common features that receptor, match along to be a perfect fit 29. involve ligand and receptor, sampling and Binding orientation of small-molecule drug scoring. Sampling entails conformational and candidates to their macromolecular targets orientational location of the ligand within the predicts the affinity and activity of a given small constraints of the receptor-site binding. A molecule 30. scoring function selects the best ligand conformation, orientation, and translation Advantages of docking 31 (referred to as poses), and classifies ligands in The application of docking in a targeted drug- rank order. A successful docking exercise must delivery system is a huge benefit. One can study accurately predict either or both ligand the size, shape, charge distribution, polarity, structure (pose prediction) and its binding hydrogen bonding, and hydrophobic propensity (affinity prediction). Available interactions of both ligand (drug) and receptor docking programs differ essentially in ligand (target site). placement in the “combining” site, exploration Molecular docking helps in the identification of of conformational space and scoring or binding target sites of the ligand and the receptor estimate37. Possible pitfalls in the docking molecule. studies are discussed and hints are provided to Docking also helps in understanding of different resolve commonly occurring problems increase enzymes and their mechanism of action. in computing power, how to improve the The “scoring” feature in docking helps in accuracy is the future 38. There three important selecting the best fit or the best drug from an aspects of protein-ligand docking: protein array of options. flexibility, ligand sampling, and scoring Not everything can be proved experimentally as functions. Rapid advances in the last two traditional experimental methods for drug decades have almost solved the ligand sampling discovery take a long time. Molecular docking issue. Speed and accuracy are the two important helps in moving the process of computer-aided characteristics of a scoring function 39. Because drug designing faster and also provides every of the rapid direction for scoring function conformation possible based on the receptor development, the computational methods for and ligand molecule. protein flexibility is still in its infancy and Docking has a huge advantage when it comes to thereby remain one of the major future the study of protein interactions. directions in protein-ligand docking. There are millions of compounds, ligands, drugs, and receptors, the 3D structure of which has CONCLUSION been crystallized. Virtual screening of these Molecular Docking is a valuable and compounds can be made. knowledgeable tool for in silico screening. It is playing an important and ever increasing role in Limitations of docking32, 33 rational Docking is a computational In protein–small-molecule docking, there can be procedure of searching for an appropriate problems in the receptor structure. A reliable ligand that fits both energetically and resolution value for small-molecule docking is geometrically the protein’s binding site and has below 1.2 Å while most crystallographic been proved very efficient tool for novel drug structures have a resolution between 1.5 and discovery for targeting protein. Among different 2.5 Å. types of docking, protein-ligand docking is of Increasing the use of homology models in special interest, because of its application in docking should be looked at with care as they medicine industry. Protein-ligand docking refers have even poorer resolution 34. Most to search for the accurate ligand conformations applications accept and yield good results for within a targeted protein when the structure of

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