Structure-based drug design: aiming for a perfect fit

Abstract

Knowledge of the three-dimensional structure of therapeutically relevant targets has informed drug discovery since the first protein structures were determined using X-ray crystallography in the 1950s and 1960s. In this editorial we provide a brief overview of the powerful impact of structure-based drug design (SBDD), which has its roots in computational and structural biology, with major contributions from both academia and industry. We describe advances in the application of SBDD for integral membrane protein targets that have traditionally proved very challenging. We emphasize the major progress made in fragment-based approaches for which success has been exemplified by over 30 clinical drug candidates and importantly three FDA-approved drugs in oncology. We summarize the articles in this issue that provide an excellent snapshot of the current state of the field of SBDD and fragment-based drug design and which offer key insights into exciting new developments, such as the X-ray free-electron laser technology, cryo-electron microscopy, open science approaches and targeted protein degradation. We stress the value of SBDD in the design of high-quality chemical tools that are used to interrogate biology and disease pathology, and to inform target validation. We emphasize the need to maintain the scientific rigour that has been traditionally associated with structural biology and extend this to other methods used in drug discovery. This is particularly important because the quality and robustness of any form of contributory data determines its usefulness in accelerating drug design, and therefore ultimately in providing patient benefit.

Keywords: drug discovery and design; pharmacology; structure.

Figure 1. Yearly growth of structures in the Protein Data Bank

Beige bars: total number of X-ray, NMR, electron microscopy and modelled structures in the PDB. Blue bars: total number of structures deposited per year. Source: RCSB Protein Data Bank: www.rcsb.org/pdb/home/home.do

Figure 2. CryoEM structure of the 20S proteasome with bound substrate analogue

The left-hand side shows a superposition of the cryoEM density map and 20S proteasome coordinates in orange (PDB accession codes EMD-2981 and 5A0Q). The close-up shows the covalently bound substrate analogue in yellow with the P1, P2 and P3 side chain positions indicated. The density map is displayed in black. Figure kindly provided by Ed Morris.

Figure 3. Crystal structure of the chemical tool CCT251545 bound to the CDK8-cyclin C complex

The inhibitor CCT251545 is shown in gold, CDK8-cyclin C is displayed in purple and key hydrogen bond interactions are shown in yellow (PDB ID code 5BNJ).