Developing Kinase Inhibitors Using Computer-Aided Drug Design Approaches

Abstract

Computational methods are useful tools to assist and interact with experiment techniques to expedite the drug design process in general. Provided here is an introduction of well-established and newly developed computer-aided drug design (CADD) approaches that are regularly being used in the development of kinase inhibitors. This includes methods from the two major CADD categories: structure-based drug design (SBDD) and ligand-based drug design (LBDD). With known three-dimensional structure of the target, SBDD approaches help to identify key structural and interaction features that are responsible for specific biological functions of the target. Such information can be utilized to design inhibitors via a number of approaches including database screening, fragment-based drug design, and ligand optimization. LBDD methods focus on known inhibitors for a target to establish a relationship between their intrinsic properties with experimental activities, termed structure-activity relationship, information that can be used for optimization of known inhibitors in order to improve their activities. In this chapter, CADD protocols from both SBDD and LBDD will be presented along with real-life examples of successful applications of these methods for kinase inhibitor discovery in our laboratory.