Kinase-likeness and kinase-privileged fragments: toward virtual polypharmacology.
Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. We investigated the phenomenon of kinase-likeness, i.e., the propensity of ligands to inhibit protein kinases, in the context of kinase-specific substructural fragments. The frequency of occurrence of multiple structural fragments in kinase inhibitor libraries relative to nonkinase compounds has been analyzed. A combination of structural fragment counts, termed the "2-0" kinase-likeness rule, provides approximately 5-fold enrichment in kinase active compounds. This rule has been validated using in-house kinase counterscreening data and applied prospectively to uncover kinase activities in marketed drugs. In addition, the role of discriminating fragments in kinase recognition was interrogated using available structural data, providing an insight into their effect on inhibitor potency and selectivity. One of these fragments, bisarylaniline, has been characterized as a kinase-privileged fragment with specific binding preferences and a link to increased activity within kinases.
Aronov
Alex M
AM
Vertex Pharmaceuticals Inc., Cambridge, Massachusets 02139-4242, USA. alex_aronov@vrtx.com
McClain
Brian
B
Moody
Cameron Stuver
CS
Murcko
Mark A
MA
D000814:Aniline Compounds / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D008024:Ligands; D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases