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. 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 453 IJPCBS 2017, 7(4), 453-458 Nagaraju Pappula et al. ISSN: 2249-9504 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). 454 IJPCBS 2017, 7(4), 453-458 Nagaraju Pappula et al. ISSN: 2249-9504 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 molecular dynamics 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