Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Medicinal, Buenos Aires, C1113AAD, Argentina; CONICET-Universidad de Buenos Aires, Instituto de la Química y el Metabolismo del Fármaco (IQUIMEFA), Buenos Aires, 1113, Argentina.
Instituto de Investigaciones Biotecnológicas "Dr. Rodolfo Ugalde" (IIBIO), CONICET, San Martín, Buenos Aires, 1650, Argentina; Escuela de Bio y Nanotecnología (EByN), Universidad Nacional de San Martín (UNSAM), San Martín, Buenos Aires, 1650, Argentina.
Eur J Med Chem. 2023 Jun 5;254:115345. doi: 10.1016/j.ejmech.2023.115345. Epub 2023 Apr 7.
Based on the activity of 23 TSCs on CZ taken from the literature, we have developed a QSAR model for predicting the activity of TSCs. New TSCs were designed and then tested against CZP, resulting in inhibitors with IC values in the nanomolar range. The modelling of the corresponding TSC-CZ complexes by molecular docking and QM/QM ONIOM refinement indicates a binding mode compatible with what was expected for active TSCs, according to a geometry-based theoretical model previously developed by our research group. Kinetic experiments on CZP suggest that the new TSCs act by a mechanism that involves the formation of a reversible covalent adduct with slow association and dissociation kinetics. These results demonstrate the strong inhibitory effect of the new TSCs and the benefit of the combined use of QSAR and molecular modelling techniques in the design of new and potent CZ/CZP inhibitors.
基于文献中从 CZ 上获得的 23 个 TSC 的活性，我们开发了一个用于预测 TSC 活性的 QSAR 模型。设计了新的 TSC 并对其进行了 CZP 测试，结果得到了具有纳摩尔范围内 IC 值的抑制剂。通过分子对接和 QM/QM ONIOM 细化对相应的 TSC-CZ 复合物进行建模，根据我们研究小组之前开发的基于几何形状的理论模型，表明与预期的活性 TSC 相兼容的结合模式。对 CZP 的动力学实验表明，新的 TSC 通过涉及与缓慢的缔合和离解动力学形成可逆共价加合物的机制起作用。这些结果证明了新的 TSC 的强烈抑制作用，以及在设计新的强效 CZ/CZP 抑制剂中结合使用 QSAR 和分子建模技术的益处。
