Molecular Mechanisms of Drug Action: X-ray Crystallography at the Basis of Structure-based and Ligand-based Drug Design

Abstract

Biological systems are recognized for their complexity and diversity and yet we sometimes manage to cure disease via the administration of small chemical drug molecules. At first, active ingredients were found accidentally and at that time there did not seem a need to understand the molecular mechanism of drug functioning. However, the urge to develop new drugs, the discovery of multipurpose characteristics of some drugs, and the necessity to remove unwanted secondary drug effects, incited the pharmaceutical sector to rationalize drug design. This did not deliver success in the years directly following its conception, but it drove the evolution of biochemical and biophysical techniques to enable the characterization of molecular mechanisms of drug action. Functional and structural data generated by biochemists and structural biologists became a valuable input for computational biologists, chemists and bioinformaticians who could extrapolate in silico, based on variations in the structural aspects of the drug molecules and their target. This opened up new avenues with much improved predictive power because of a clearer perception of the role and impact of structural elements in the intrinsic affinity and specificity of the drug for its target. In this chapter, we review how crystal structures can initiate structure-based drug design in general.