Schrödinger デジタル創薬セミナー: Into the Clinic ~計算化学がもたらす創薬プロセスの変貌~ 第2回


Aleksey Gerasyuto
Vice President, Drug Discovery, Head of Chemistry, Schrödinger Therapeutics Group


Inhibitors of integrin αvβ6 have the potential to treat fibrotic disease through blockage of the TGFβ pathway. At Morphic Therapeutic, we investigated a series of zwitterionic alpha amino acid αvβ6 inhibitors in a structurally enabled program using a variety of in silico techniques combined with traditional medicinal chemistry approaches. The main challenges to overcome in the program were obtaining sufficient permeability for oral bioavailability and sufficient αvβ6 potency and selectivity over related integrins αvβ1 and αvβ8. Highly permeable compounds were obtained by identifying structures that could adopt a shielded conformation with reduced amine basicity. These efforts were enhanced by computational modeling and QM based pKa predictions. In the optimization of potency and selectivity, Free Energy Perturbation (FEP+) proved to be a valuable tool for prioritizing compounds for synthesis. The in vivo half-life of the compounds was optimized using a cassette PK screening approach. The program resulted in the discovery of MORF-627, a highly potent and selective αvβ6 inhibitor development candidate with projected once daily oral human dosing.