AI-powered platform discovers PHD inhibitor for anemia treatment

A study published in the Journal of Medicinal Chemistry reports the discovery of a novel PHD inhibitor for the treatment of anemia.

This academic advancement is based on Chemistry42, InSilico Medicine’s proprietary generative chemistry platform, comprised of more than 40 selected generative models.

As suggested in previous studies, inhibition of prolyl hydroxylase domain (PHD) enzymes influences fundamental biological processes, including red blood cell production, by regulating the HIF-α pathway, thereby indicating the potential for treating anemia. induced by CKD.

Guided by a structure-based drug discovery (SBDD) strategy, Insilico scientists gathered structural information on the PHD target and known molecules and generated a series of candidate molecules using chemistry42. Using built-in filters covering drug resemblance, pharmacophore indices, synthesis evaluation, etc., AI-generated candidates were ranked and prioritized before a blockbuster compound was produced for further optimization.

“Through Chemistry42, we received end-to-end support from molecule generation to compound selection,” said Xiaoyu Ding, the computational chemist sharing lead authorship. “With the power of generative artificial intelligence, we could accelerate the drug discovery process without compromising novelty or quality.”

Subsequently, several rounds of synthetic assay optimization yielded lead compound 15, which demonstrated a favorable in vitro/in vivo ADMET profile, clean safety profile, and promising PK properties in multiple species. Additionally, the compound was shown to alleviate anemia in a rat disease model with relatively simple synthesis steps.

“Since more than 10% of the world’s population suffers from CKD, Insilico’s new molecule could be useful for further research and for patients around the world,” said Jianyu Xu, the co-medicinal chemist. author of the article. “After extensive research into PHD inhibitors already available on the market, we hope to develop a new non-carboxylic acid molecule with better permeability and PK profiles.”