Computer-assisted selective optimization of side-activities - from cinalukast to a PPAR α modulator.

Computer-assisted selective optimization of side-activities - from cinalukast to a PPARα modulator. ChemMedChem. 2019 May 29;: Authors: Pollinger J, Schierle S, Neumann S, Ohrndorf J, Kaiser A, Merk D Abstract Automated computational analogue design and scoring can speed up hit-to-lead optimization and appears particularly promising in selective optimization of side-activities (SOSA) where possible analogue diversity is confined. Probing this concept, we employed the CysLT1R antagonist cinalukast as lead for which we discovered PPARα modulatory activity. We automatically generated a virtual library of close analogues and classified these approx. 8000 compounds for PPARα agonism and CysLT1R antagonism using automated affinity scoring and machine learning. A computationally preferred analogue for SOSA was synthesized and in vitro characterization indeed revealed a marked activity shift towards enhanced PPARα activation and diminished CysLT1R antagonism. Thereby, this prospective application study highlights the potential of automating SOSA. PMID: 31141287 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research