Structure‐Based Drug Design

Abstract

Structure‐based drug design (SBDD) is the backbone of modern pharmaceutical research and development. Its origins date back to the 1950s and 1960s when the first X‐ray protein structures and pioneering studies correlating ligand–receptor binding and drug activity came out. With this foundation, seminal work on computer graphics enabled the first visualization and manipulation of virtual protein structures. These milestones opened the avenues for the growth of protein crystallography and molecular modeling, which thenceforth evolved side by side to culminate in modern SBDD. Today, SBDD can handle molecular targets previously regarded as intractable or undruggable, such as protein–protein interactions. Another advance coming from SBDD, fragment‐based drug discovery has excelled in optimizing weak ligands into drug‐like compounds. SBDD has provided groundbreaking drugs for many therapeutic areas, including highly complex conditions and diseases that were previously considered a death sentence. In fact, a substantial fraction of the drugs approved recently have been developed with the support of structural data. This article provides a perspective on the central aspects of this exciting field and explores the fundamentals of molecular modeling and its integration with X‐ray diffraction. The discussion of key concepts is followed by representative examples of the practice of SBDD.

Editorial: Chemoinformatics Approaches to Structure- and Ligand-Based Drug Design, Volume II

“…The workflow proved to be feasible in removing or reducing biases in the classification of druggable pockets. Virtual screening has become an important tool in drug discovery as it allows a preliminary evaluation of large compound collections in short timelines and costs ( Ferreira and Andricopulo, 2021 ). A novel virtual screening workflow ( Venkatraman et al ) that can sample billions of compounds and supports parallel and cloud computing is reported.…”