Molecular modelling

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Drug design is an iterative process which begins when a chemist identifies a compound that displays an interesting biological profile and ends when both the activity profile and the chemical synthesis of the new chemical entity are optimized. Traditional approaches to drug discovery rely on a step-wise synthesis and screening program for large numbers of compounds to optimize activity profiles. Over the past ten to twenty years, scientists have used computer models of new chemical entities to help define activity profiles, geometries and reactivity. This article introduces the concepts of molecular modelling and contains references for further reading. One of the basic tenets of medicinal chemistry is that biological activity is dependent on the three-dimensional placement of specific functional groups (the pharmacophore). Over the past few years, advances in the development of new mathematical models which describe chemical phenomena and development of more intuitive program interfaces coupled with the availability of faster, smaller and affordable computer hardware have provided experimental scientists with a new set of computational tools. These tools are being successfully used, in conjunction with traditional research techniques, to examine the structural properties of existing compounds, develop and quantify a hypothesis which relates these properties to observed activity and utilize these "rules" to predict properties and activities for new chemical entities. The development of molecular modeling programs and their application in pharmaceutical research has been formalized as a field of study known as computer assisted drug design (CADD) or computer assisted molecular design (CAMD). Computational chemistry/molecular modeling is the science (or art) of representing molecular structures numerically and simulating their behavior with the equations of quantum and classical physics. Computational chemistry programs allow scientists to generate and present molecular data including geometries (bond lengths, bond angles, torsion angles), energies (heat of formation, activation energy, etc.), electronic properties (moments, charges, ionization potential, electron affinity), spectroscopic properties (vibrational modes, chemical shifts) and bulk properties (volumes, surface areas, diffusion, viscosity, etc.). As with all models however, the chemist's intuition and training is necessary to interpret the results appropriately. Comparison to experimental data, where available, is also important to guide both laboratory and computational work. The starting point for many computer assisted molecular design (CAMD) studies is generally a two dimensional drawing of a compound of interest. These diagrams can range from notebook or "back-of-the-envelope" sketches to electronically stored connection tables in which one defines the types of atoms in the molecule, their hybridization and how they are bonded to each other. All bio molecular modelling is sometimes encountered among experimentalists even today; equally misguided is a blind acceptance of modelling results without critical analysis. However, Demonstrations of the practical contribution made by bio molecular modelling have led to a growing recognition of its worth. This is a fertile and growing area, with exciting opportunities and an enormous range of potential applications. It is crucial for the bio molecular modeller to understand the issues of interest to biologists, the complexity of biological systems and how to tackle them effectively by modelling. Vast amounts of data are being provided by large-scale research efforts in genomics, proteomics, glycomics and structural biology. The challenge for bio molecular modelling is to help in efforts to use these diverse data to develop new drugs, therapies, catalysts and biologically based nanotechnology. Molecular modelling and simulation methods are increasingly making important and indeed often uniquely detailed contributions to the study of the structure and function of biological macromolecules. Applications include studies of protein folding and conformational changes (Daggett 2006; Elcock 2006), association of proteins with small molecules (Moitessier et al. 2008) or other proteins (McGuffee & Elcock 2006; Ritchie 2008), structure-based drug design (Taft et al.2008), computation of binding free energies for ligands (Gilson & Zhou 2007), modelling the dynamics of ion channels and transport across membranes (Beckstein et al. 2003) and modelling and analysis of enzyme mechanisms (Warshel et al. 2006b; Mulholland 2008). This last area (biological catalysis), for example, is fascinating from a chemical point of view, and is an important interface between chemistry and biology. Improvements in computer hardware continue to deliver more computational power, which, when combined with theoretical and algorithmic developments, have led to an increasing range and

depth of applications of molecular modelling in biology. Indeed, the whole field of bio molecular modelling is now too large to be reasonably covered in a single review. Here, the focus is on atomistic molecular simulation, in particular of proteins. The field of bio molecular simulation is still evolving, and it is not yet at the stage where quantitative, exact predictions, of (for example) relative binding free energies, reaction rates or the effects of mutation, can routinely be made (Van Gunsteren et al. 2006). For this reason, it is important to try to link with experiment to validate predictions from modelling: prediction of pKa values of functional groups in proteins provides a useful and demanding example of this type of test (Nielsen & McCammon 2003; Jensen et al. 2005; Warshel et al.2006a; Stanton & Houk 2008; Bas et al. 2008). All proteins share the same backbone, with their structure and function determined solely by the side chains of the 20 different amino acids. Therefore, a precise modelling of residue-residue and residue-backbone interactions is a crucial aspect in computational evaluation of proteins. Computational methods rely on a potential function to evaluate the interactions within proteins [1]. In general, two types of the potential functions currently exist: physics-based [2-4] and knowledge-based [5].Knowledge-based potentials (KBP) derive statistical preferences on different features from structural and sequence databases and implicitly capture. In general, a two-step process. First, a detailed model of a protein or protein complex is built, and then, in the second step, its energetic characteristics are evaluated. The second step, however, would require dealing with additivity and independence of the terms as well as accounting for additional factors like interaction with water, entropic effects, and backbone flexibility.