Drugability of extracellular targets: discovery of small molecule drugs targeting allosteric, functional, and subunit-selective sites on GPCRs and ion channels.
Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and gamma-aminobutyric acid receptors, and the Ca(V)2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.
Grigoriadis
Dimitri E
DE
Neurocrine Biosciences Inc., San Diego, CA 92130, USA. dgrigoriadis@neurocrine.com
Hoare
Samuel R J
SR
Lechner
Sandra M
SM
Slee
Deborah H
DH
Williams
John A
JA
D000494:Allosteric Regulation; D001665:Binding Sites; D002493:Central Nervous System Diseases / Q000188:drug therapy; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D016503:Drug Delivery Systems; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism
D007473:Ion Channels; D043562:Receptors, G-Protein-Coupled; D018079:Receptors, GABA; D003346:Corticotropin-Releasing Hormone