3D Structure and Drug Design

Abstract

The knowledge of the three-dimensional (3D) structure of the macromolecules and of their complexes plays a major role in the discovery of potential novel lead compounds and drugs and in the characterization of the biochemical mechanisms underlying the pharmacological and biological activity. Given that this information driven process is grounded on the experimental or computational determinations of the 3D structures, this chapter begins with a description of the core methodologies that allow one to obtain 3D structural data and to assess their quality. The impact of structural genomics is then summarized, with specific emphasis on both the technological progress and the molecular biology achievements brought by these high-throughput initiatives during the last decade. Then, the attention is focused on the computational techniques intended for inferring pharmaco-biological information from 3D structural data. Recently designed approaches for structure-based annotations, computational docking, 3D structure-based virtual screening, and interactome analysis are described, with particular accent on the advances over previous methods and on their intrinsic limitations. Few practical examples are provided to illustrate the state of the art of these methodologies. The more recently underscored intrinsically disordered proteins and conformational diseases are eventually described, pointing the attention toward the interplay between biophysical, biochemical, and bioinformatics approaches.