Abstract
Proteins, which are the most common drug targets, are flexible and can exist in various conformers that are energetically competitive. Hence, it is crucial to consider its dynamic behavior. Most notable methods that incorporate flexibility of protein are discussed here. Structural knowledge of molecular targets (or drug receptors), usually proteins, has transformed the drug design process in the last three decades or so. While most of the drugs that were discovered 30 years ago are by serendipity and ‘trial and error’, rational drug design approaches are more focused. Rational drug design techniques use structure of the drug receptor or structure of ligands that are shown to bind to the target to identify potential drug candidates. Approaches that use the structure of drug receptor for drug discovery are referred to as structure based drug design (SBDD). X-ray crystallography and NMR spectroscopy have been in the forefront in protein structure determination. Several computational methods have been developed and new methods are being proposed for protein structure prediction from the primary sequence (for eg. homology modeling); however, they suffer from several caveats. Currently, use of SBDD has become a standard exercise as part of drug discovery and development both in industry and academia. Typically, the process involves obtaining the structure of the target protein; identification of active site; virtual screening of a small molecule database (containing chemically diverse structures of small molecules in the order of a million) and identification of potential ligands based on a chosen scoring function. Ideally, docking process involved in virtual screening and calculating the binding energy should allow the protein and the ligand to change their conformations to effectively bind to each other. Ligands being smaller compounds (typically containing tens of nonhydrogen atoms), their conformational changes can be modeled with reasonable accuracy. However, explicit modeling of protein flexibility involves a lot of computer time especially considering that a million compounds have to be screened and hence is not feasible. In short, a compromise between ‘quick answer’ and ‘right answer’ is made in docking calculations for practical applications. Recently, allowing protein to be flexible at least partially has become possible, thanks to development of efficient algorithms and, availability of faster processors, larger storage and RAM. Several approximations have been proposed to accommodate protein flexibility of which few of the notable ones are discussed in the article. The readers are suggested to refer additional resources on structure based drug design, which are given at the end.
