AI-Powered Platform Identifies PHD Inhibitor for Treating Anemia

The discovery, as detailed in the Journal of Medicinal Chemistry, was made possible by Chemistry42, a proprietary generative chemistry platform developed by InSilico Medicine. This platform consists of over 40 carefully selected generative models.

Previous studies have indicated that inhibiting prolyl hydroxylase domain enzymes (PHD) can have a significant impact on crucial biological processes, such as the production of red blood cells. By regulating the HIF-α pathway, these enzymes play a role in CKD-induced anemia, making them potential targets for treatment.Using a structure-based drug discovery (SBDD) approach, InSilico’s scientists collected structural information on the PHD target and known molecules. With the assistance of Chemistry42, they generated a series of molecule candidates. These AI-generated candidates were then ranked and prioritized using various filters, including drug-likeness, pharmacophore clues, and synthesis evaluation. Eventually, a hit compound was identified for further optimization.

Xiaoyu Ding, a computational chemist and co-author of the study, expressed gratitude for Chemistry42’s support throughout the entire process, from molecule generation to hit compound selection. The power of generative artificial intelligence enabled them to expedite the drug discovery process without compromising on novelty or quality.Through several rounds of synthesis test optimization, lead compound 15 was developed. This compound exhibited a favorable in vitro/in vivo ADMET profile, a clean safety profile, and promising PK properties across multiple species. Furthermore, it was proven to alleviate anemia in a rat disease model through a relatively straightforward synthesis process.

Jianyu Xu, a medicinal chemist and co-author of the paper, highlighted the significance of InSilico’s novel molecule, considering that over 10% of the global population suffers from CKD. The researchers aim to develop a noncarboxylic acid molecule with improved permeability and PK profiles, building upon their comprehensive research on existing PHD inhibitors in the market. This molecule holds potential for further investigations and could benefit patients worldwide.

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