Structure-based drug discovery and protein targets in the CNS

TY - JOUR

T1 - Structure-based drug discovery and protein targets in the CNS

AU - Hubbard, Roderick E.

PY - 2011/1

Y1 - 2011/1

N2 - Structure-based methods are having an increasing role and impact in drug discovery. The crystal structures of an increasing number of therapeutic targets are becoming available. These structures can transform our understanding of how these proteins perform their biological function and often provide insights into the molecular basis of disease. In addition, the structures can help the discovery process. Methods such as virtual screening and experimental fragment screening can provide starting hit compounds for a discovery project. Crystal structures of compounds bound to the protein can direct or guide the medicinal chemistry optimisation to improve drug-like properties - not only providing ideas on how to improve binding affinity or selectivity, but also showing where the compound can be modified in attempting to modulate physico-chemical properties and biological efficacy. The majority of drug discovery projects against globular protein targets now use these methods at some stage.This review provides a summary of the range of structure-based drug discovery methods that are in use and surveys the suitability of the methods for targets currently identified for CNS drugs. Until recently, structure-based discovery was difficult or unknown for these targets. The recent determination of the structures of a number of GPCR proteins, together with the steady increase in structures for other membrane proteins, is opening up the possibility for these structure-based methods to find increased use in drug discovery for CNS diseases and conditions. (C) 2010 Elsevier Ltd. All rights reserved.

AB - Structure-based methods are having an increasing role and impact in drug discovery. The crystal structures of an increasing number of therapeutic targets are becoming available. These structures can transform our understanding of how these proteins perform their biological function and often provide insights into the molecular basis of disease. In addition, the structures can help the discovery process. Methods such as virtual screening and experimental fragment screening can provide starting hit compounds for a discovery project. Crystal structures of compounds bound to the protein can direct or guide the medicinal chemistry optimisation to improve drug-like properties - not only providing ideas on how to improve binding affinity or selectivity, but also showing where the compound can be modified in attempting to modulate physico-chemical properties and biological efficacy. The majority of drug discovery projects against globular protein targets now use these methods at some stage.This review provides a summary of the range of structure-based drug discovery methods that are in use and surveys the suitability of the methods for targets currently identified for CNS drugs. Until recently, structure-based discovery was difficult or unknown for these targets. The recent determination of the structures of a number of GPCR proteins, together with the steady increase in structures for other membrane proteins, is opening up the possibility for these structure-based methods to find increased use in drug discovery for CNS diseases and conditions. (C) 2010 Elsevier Ltd. All rights reserved.

KW - Structure-based drug discovery

KW - Fragment-based drug discovery

KW - Protein structure

KW - Protein-ligand interactions

KW - STRUCTURE-BASED DESIGN

KW - X-RAY-STRUCTURE

KW - CRYSTAL-STRUCTURE

KW - ESTROGEN-RECEPTOR

KW - LIGAND-BINDING

KW - BETA(2)-ADRENERGIC RECEPTOR

KW - THERAPEUTIC TARGETS

KW - NICOTINIC RECEPTORS

KW - MOLECULAR-DYNAMICS

KW - COUPLED RECEPTOR

UR - http://www.scopus.com/inward/record.url?scp=78149501220&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2010.07.016

DO - 10.1016/j.neuropharm.2010.07.016

M3 - Literature review

SN - 0028-3908

VL - 60

SP - 723

JO - NEUROPHARMACOLOGY

JF - NEUROPHARMACOLOGY

IS - 1

ER -