Benefits of Structural Genomics for Drug Discovery Research

Abstract

While three dimensional structures have long been used to search for new drug targets, only a fraction of new drugs coming to the market has been developed with the use of a structure-based drug discovery approach. However, the recent years have brought not only an avalanche of new macromolecular structures, but also significant advances in the protein structure determination methodology only now making their way into structure-based drug discovery. In this paper, we review recent developments resulting from the Structural Genomics (SG) programs, focusing on the methods and results most likely to improve our understanding of the molecular foundation of human diseases. SG programs have been around for almost a decade, and in that time, have contributed a significant part of the structural coverage of both the genomes of pathogens causing infectious diseases and structurally uncharacterized biological processes in general. Perhaps most importantly, SG programs have developed new methodology at all steps of the structure determination process, not only to determine new structures highly efficiently, but also to screen protein/ligand interactions. We describe the methodologies, experience and technologies developed by SG, which range from improvements to cloning protocols to improved procedures for crystallographic structure solution that may be applied in "traditional" structural biology laboratories particularly those performing drug discovery. We also discuss the conditions that must be met to convert the present high-throughput structure determination pipeline into a high-output structure-based drug discovery system.

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

“…This dynamic equilibrium has functional importance, participating in such processes as the diffusion of oxygen into the heme cavity of myoglobin, the diffusion of ions across ion channels, substrate binding, and ion channel gating [4]. Here, we first highlighted the contribution of in silico receptor modeling, a critical process that aims to ease one of the major bottlenecks of structure-based drug discovery: limited availability of experimental protein structures [5,6]. Despite the lower resolution than experimental counterparts, using protein models as the starting point has already achieved great successes in current pharmaceutical industry.…”

“…To reach the pocket formed by two coplanar Tyr907 and Tyr896, amide edge was extended to [5,6,6]-tricyclic indole lactam or [5,6,7]tricyclic indole lactam. Their model predicted a high binding affinity with [5,6,7]-tricyclic indole lactam, and later crystal structure showed that this crucial amide is locked in a cis conformation in this seven-member lactam ring, thus strengthening the interaction. In addition, the 2-phenyl group interacted with Tyr907 and Tyr896 via -stacking, as the design proposed [227].…”

Crystal Structure of Shigella flexneri SF173 Reveals a Dimeric Helical Bundle Conformation

“…Structural genomics, which aims for functional identification of genes (genome) through structure-based analyses of the gene products (proteome), has the additional benefit of frequently leading to the discovery of novel drug target proteins [1,2]. Here, we report the structural analysis of SF173, one of the targets chosen for our laboratory-scale structural genomics approach to the human enteropathogenic bacterium Shigella flexneri.…”

“…Antibiotics have been considered alternatives for shigellosis treatment, but the appearance of antibiotic-resistant S. flexneri has been recently reported [9,10], raising an urgent need for novel antibiotics to treat the infection. In terms of novel antibiotic development, structural genomics can contribute to identification of a novel, unique drug target molecule via structure-function analysis of previously uncharacterized proteins [2,11]. In addition, detailed structural information obtained from structural genomics study enables us to quickly and efficiently discover novel agents by structure-based rational drug design for targeting the newly validated proteins [11].…”

A public database of macromolecular diffraction experiments

“…However, at present, automatic re-refinement is likely to fail when the deposited atomic coordinates have significant errors. Moreover, automatic rerefinement does not correct situations in which ligands are misidentified and/or misplaced (Cooper et al, 2011;Grabowski et al, 2009;Zheng, Hou et al, 2014). Recent analyses have shown that a significant number (around 15%) of metal ions reported in the PDB are misassigned and/or incorrectly modeled (Zheng, Chordia et al, 2014).…”