Enhanced hit-to-lead process using bioanalogous lead evolution and chemogenomics: application in designing selective matrix metalloprotease inhibitors

The authors describe an innovative approach for designing novel inhibitors. This approach effectively integrates the emerging chemogenomics concept of target-family-based drug discovery with bioanalogous design strategies, including privileged structures, molecular frameworks as well as bioisosteric and bioanalogous/isofunctional modifications.The authors applied this method in the design of selective inhibitors of matrix metalloproteases (MMPs), also referred to as matrixins, on the basis of a unique analysis of the ligand–target knowledge base, the ‘matrixinome’. For this analysis, the authors created an annotated MMP database containing ∼ 300 inhibitors with their published activity profile. The ligand space was then arranged into a lead evolution tree, where the substructural transformations in each virtual step led to marked changes in the activity pattern. This allowed subtype-specific privileged fragments to be extracted as well as modifications, which improve activity and/or selectivity. Furthermo...