The role of ligand efficiency metrics in drug discovery.
The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Andrew L
AL
Hopkins
Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Magyar Tudósok körútja 2., 1525 Budapest, PO Box 17, Hungary.
György M
GM
Keserü
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
Paul D
PD
Leeson
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
David C
DC
Rees
Gfree Bio, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, USA.
Charles H
CH
Reynolds
D000284:Administration, Oral; D055598:Chemical Phenomena; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D008024:Ligands; D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries