A new PHD inhibitor for the treatment of anemia has been discovered, according to a study published in the Journal of Medicinal Chemistry.
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Chemistry42, a unique generative chemistry platform developed by InSilico Medicine that includes over 40 carefully chosen generative models, powers this platform.
Previous research has indicated that inhibiting prolyl hydroxylase domain enzymes (PHD) can regulate the HIF-α pathway, which in turn affects basic biological processes such as the generation of red blood cells. This suggests that PHD could be used as a treatment for anemia caused by CKD.
With the aid of Chemistry42, Insilico’s scientists produced several molecule candidates by gathering structural data on the PHD target and existing compounds, all in accordance with a structure-based drug discovery (SBDD) approach.
Before a hit compound was created for additional optimization, the AI-generated compounds were sorted and prioritized using built-in filters, including drug-likeness, pharmacophore clues, synthesis assessment, and more.
Thanks to Chemistry42, we had end-to-end assistance from molecule generation to hit compound selection. With the power of generative artificial intelligence, we could accelerate the drug discovery process without compromises in novelty or quality.
Xiaoyu Ding, Study First Author, InSilico Medicine
Lead compound 15, which showed a positive in vitro/in vivo ADMET profile, a clear safety profile, and promising PK characteristics in various species, was the result of numerous rounds of synthesis test optimization. Furthermore, the compound’s very easy production procedures were demonstrated to reduce anemia in a rat disease model.
Given that more than 10% of the global population suffers from CKD, Insilico’s novel molecule could be meaningful for further investigations and patients worldwide. After comprehensive research into PHD inhibitors already available on the market, we hope to develop a novel noncarboxylic acid molecule for better permeability and PK profiles.
Jianyu Xu, Study Co-Author, InSilico Medicine
Journal Reference:
Xu, J., et. al. (2024) Discovery of Novel and Potent Prolyl Hydroxylase Domain-Containing Protein (PHD) Inhibitors for The Treatment of Anemia. Journal of Medicinal Chemistry. doi:10.1021/acs.jmedchem.3c01932