MOLECULAR DOCKING AND DRUG DISCOVERY Introduction

Drug discovery is the process of identifying new compounds with therapeutic values. The process is an elaborate one and often requires an in-depth knowledge of the nature of the compound that is being studied. There are numerous natural compounds available, which possess a therapeutic property, but require proper understanding of the compound. This includes the study of the active substance that really gives the drug like property, the nature of the active substance in the compound, the structure of the active substance and also the exact structure activity relationship it possess. The choice of lead structures is very important for success in drug development. Most of the drugs are developed based on the lead compounds derived from primary lead compound structures by screening them from natural and synthetic compounds. Studies of the biological and biochemical mechanisms of diseases have provide information on the macromolecules to be targeted and also the types of molecules needed for the new development of drugs. Since the advancement in the techniques like protein isolation, purification numerous macromolecules have been sequenced and structures have been elucidated has increased the need of elucidating their functions too. This informations about the protein sequence and structure are very useful in the understanding of the interaction of the proteins with the lead compounds. A drug molecule manifests its activity through binding to a receptor macromolecule. As the interaction arises from the 3D structure from both the molecules the 3D structural knowledge of these molecules is very crucial for drug discovery and designing new lead molecules. Computers and computer assisted methods are very much useful to handle the 3D structures of the protein and the ligand. They assist in the visualizations of the molecules, to study the type of interactions they possess over each other, to simulate the interaction process, to analyze the stable structures, to analyze the physical properties of the molecules. In order to exhibit biological activities, molecules should be able to reach the receptor site in the body and bind to the target receptor. Computer and computer graphics have become essential tools in rational drug design. There should be a significant complementarity in the molecular shape and properties between a drug molecule and the receptor molecule. Since there is an increase in the availability of receptor structures because of the advancement in sequencing and structure elucidation using X-ray, NMR and molecular modeling methods, rational drug designing with known receptor structures is made simpler and easier. At this point in the drug designing process, the molecular docking shows to be very helpful. Molecular docking is the Insilco method used for the study of bimolecular interactions. It is one of the amazing methods used for understanding the process of bimolecular interactions of how molecules unite to form complex structures. Molecular docking studies are vastly used to analyze the binding between molecules like protein with ligands like drugs, ions, peptides etc. This study has one of the major roles in drug discovery and development process. The most important application of docking software is virtual screening. In virtual screening the most interesting and promising molecules are selected from an existing database for further research.

Molecular Docking methods

The docking methods are based on the problem encountered for the binding analysis. The biomolecules in nature interact in a complex way to attain a complex structure which is active and whose energy is stable. Docking method can therefore be used not only to predict possible binders or inhibitors, but also to predict how strong the association between the molecules (called the binding affinity) can be. It is useful to know the binding strength (binding energy) for comparing (ranking) a group of compounds or derivatives to determine which derivative is the best binder or inhibitor. This entire molecular association process is mimicked using the docking softwares were we allow the two molecules to interact and try to understand the mode of interaction that takes place. The various docking methods currently followed are; _ Molecular dynamics _ Monte Carlo methods _ Genetic algorithms _ Fragment-based methods _ Point complementary methods _ Distance geometry methods _ Tabu searches _ Systematic searches The simulation of the docking between receptor and known drug, natural ligands or imaginary compounds is one of the most important techniques in drug designing. The docking study is able to forecast the active conformations and the functional group of the ligand. The Hbond donor-acceptor pairs, electrostatically positive-negative pairs, hydrophobic pairs are the few parameters that can be predicted with the molecular docking studies of the protein and ligand. There are two general methods in docking, were one method is flexible docking and the other is rigid docking. Flexible docking allows the ligand to rotate freely to accommodate itself in the receptor target. The other method does not allow this free rotation of the ligand to accommodate in the receptor protein. The ultimate goal of docking study is to obtain the global energy minimum model of the docking molecules. All degrees of freedom are given for the ligand molecules, to accommodate itself in the receptor molecule, so that the resultant structure as a complex is energetically stable. The energy calculations and the concepts associated with the 3D structure evaluation are achieved by the molecular mechanics approaches. Total energy is represented by set of potential energy functions. In addition to these functions, a set of parameters is also needed to compute the total energy. There are various softwares that are available for molecular docking. Examples Autodock, Dock, FlexX, Glide, InsightII.