Discovering highly selective and diverse PPAR-delta agonists by ligand based machine learning and structural modeling

Benny Da’adoosh, David Marcus, Anwar Rayan, Fred King, Jianwei Che, Amiram Goldblum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

PPAR-δ agonists are known to enhance fatty acid metabolism, preserving glucose and physical endurance and are suggested as candidates for treating metabolic diseases. None have reached the clinic yet. Our Machine Learning algorithm called “Iterative Stochastic Elimination” (ISE) was applied to construct a ligand-based multi-filter ranking model to distinguish between confirmed PPAR-δ agonists and random molecules. Virtual screening of 1.56 million molecules by this model picked ~2500 top ranking molecules. Subsequent docking to PPAR-δ structures was mainly evaluated by geometric analysis of the docking poses rather than by energy criteria, leading to a set of 306 molecules that were sent for testing in vitro. Out of those, 13 molecules were found as potential PPAR-δ agonist leads with EC50 between 4–19 nM and 14 others with EC50 below 10 µM. Most of the nanomolar agonists were found to be highly selective for PPAR-δ and are structurally different than agonists used for model building.

Original languageAmerican English
Article number1106
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

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