Structural genomics and drug discovery

Abstract

Structure determination has already proven useful for lead optimization and direct drug design. The number of high-resolution structures available in public databases today exceeds 30,000 and will definitely aid in structure-based drug design. Structural genomics approaches covering whole genomes, topologically similar proteins or gene families are great assets for further progress in the development of new drugs. However, membrane proteins representing 70% of current drug targets are poorly characterized structurally. The problems have been related to difficulties in obtaining large amount of recombinant membrane proteins as well as their purification and structure determination. Structural genomics has proven successful in developing new methods in areas from expression to structure determination by studying a large number of target proteins in parallel.

Identification of Specific Lipid-binding Sites in Integral Membrane Proteins

“…The significance of membrane proteins that constitute ϳ25% of genomic sequences (19) is not reflected in the number of membrane structures that are currently available in the Protein Data Bank. Yet membrane proteins represent 70% of current drug targets (60). Specific lipid-binding residues may therefore also present a yet unexplored area for drug targeting.…”

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…Even though the number of structures in the PDB has been increasing over the last ten years, partially thanks to structural genomics initiatives aimed to accelerate the characterization of unknown representative structures [25,26], the gap between annotated sequences and 3D protein M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT structures is still very large, mainly due to the progress in DNA sequencing technology [27]. This gap is actually even larger when considering the level of redundancy within the PDB, and the underrepresentation of certain families such as membrane proteins, in spite of the recent impressive achievements to solve structures for ~30 different G protein-coupled receptors (GPCRs) [28,29].…”

High‐Throughput Cloning and Expression of Integral Membrane Proteins in Escherichia coli

“…This can facilitate other research efforts in the field of protein structures including drug development, functional analyses and antibody development (Skolnick et al , 2000; Lundstrom, 2006a, 2007; Weigelt, 2010). …”