Docking-based virtual screening of covalently binding ligands: an orthogonal lead discovery approach.
In pharmaceutical industry, lead discovery strategies and screening collections have been predominantly tailored to discover compounds that modulate target proteins through noncovalent interactions. Conversely, covalent linkage formation is an important mechanism for a quantity of successful drugs in the market, which are discovered in most cases by hindsight instead of systematical design. In this article, the implementation of a docking-based virtual screening workflow for the retrieval of covalent binders is presented considering human cathepsin K as a test case. By use of the docking conditions that led to the best enrichment of known actives, 44 candidate compounds with unknown activity on cathepsin K were finally selected for experimental evaluation. The most potent inhibitor, 4-(N-phenylanilino)-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile (CP243522), showed a K(i) of 21 nM and was confirmed to have a covalent reversible mechanism of inhibition. The presented approach will have great potential in cases where covalent inhibition is the desired drug discovery strategy.
MSD Animal Health Innovation GmbH, Zur Propstei, D-55270 Schwabenheim, Germany.
Jörg
J
Schröder
Anette
A
Klinger
Frank
F
Oellien
Richard J
RJ
Marhöfer
Michael
M
Duszenko
Paul M
PM
Selzer
D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D016208:Databases, Factual; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry*; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry*
D008024:Ligands; D054852:Small Molecule Libraries; D013882:Thiosemicarbazones; D014227:Triazines; D056657:Cathepsin K