ポリオール経路におけるTyr48との重要な相互作用解明を目的としたチアゾリジンジオン誘導体のインデュースドフィットドッキング・ファルマコフォアモデリング・分子動力学シミュレーション研究
A computational study was conducted to characterize key binding interactions at Tyr48 within aldose reductase (ALR), an enzyme central to the polyol pathway. A structurally and energetically validated ALR-NADP+ complex was constructed via homology modeling. A statistically robust five-point pharmacophore model was derived from 54 thiazolidinedione derivatives, demonstrating strong internal and external predictive capacity. Both rigid and induced fit docking protocols were applied to ALR with and without the NADP+ cofactor. Inclusion of NADP+ reduced false-positive inhibitor placement in the cofactor binding region and clarified hydrogen bond interactions involving Tyr48. Molecular dynamics simulations revealed conformational changes at Tyr48 and Asp43 during enzyme-inhibitor complex formation, highlighting the role of Tyr48 in sustaining inter- and intramolecular hydrogen bonds. Newly designed thiazolidinedione analogs exhibited improved binding profiles relative to existing derivatives, supporting the utility of this integrated computational workflow for ALR inhibitor optimization.
Thiazolidinedione derivatives form hydrogen bonds with Tyr48 and Asp43 in aldose reductase; inclusion of the NADP+ cofactor during docking reduces non-specific binding, and molecular dynamics simulations confirm Tyr48's role in stabilizing inter- and intramolecular interactions within the enzyme-inhibitor complex.
This is basic research at the cellular or molecular level. For human application, inhalation is the most promising delivery route, but inhalation carries explosion risk and concentration matters (empirical LFL of 10%; high-concentration devices are not recommended).
See also:
https://h2-papers.org/en/papers/24974084