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Computer-Assisted Selective Optimization of Side-Activities-from Cinalukast to a PPARα Modulator

Computer-Assisted Selective Optimization of Side-Activities-from Cinalukast to a PPARα Modulator

Julius Pollinger, Simone Schierle, Sebastian Neumann, Julia Ohrndorf, Astrid Kaiser, Daniel Merk

ChemMedChem. 2019 Jul 17;14(14):1343-1348.

PMID: 31141287

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 cysteinyl leukotriene receptor 1 (CysLT1 R) antagonist cinalukast as lead for which we discovered peroxisome proliferator-activated receptor α (PPARα) modulatory activity. We automatically generated a virtual library of close analogues and classified these roughly 8000 compounds for PPARα agonism and CysLT1 R 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 toward enhanced PPARα activation and diminished CysLT1 R antagonism. Thereby, this prospective application study highlights the potential of automating SOSA.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP128312516	Cinalukast		128312-51-6	Price

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