Olaposi Omotuyi I, Oyekanmi Nash, Ojo Ayodeji A, Eniafe Gabriel O
Center for Bio-Computing and Drug Development, Adekunle Ajasin University, Akungba-Akoko, Ondo State Nigeria.
Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja.
Drug Res (Stuttg). 2019 Dec;69(12):643-649. doi: 10.1055/a-0807-8640. Epub 2019 Aug 14.
Membrane-bound transcription factor site-1 protease (S1P) is an emerging clinical target due to its roles in lipogenesis, lysosomal biogenesis, unfolded protein response and viral glycoprotein processing. In this study, homology model of S1P was created in order to understand the structural basis for S1P inhibition by PF429242 using molecular docking, molecular dynamics simulation and in silico kinetics studies. PF429242 was docked (GlideScore=-5.20 kcal/mol) into the catalytic triad (D218, H249 and S414) and validated (R=0.5686). The reversible binding kinetic parameter (K/K) was estimated at=7.28E- M with fully bound and apo-states interspersed by 3 transient ligand-bound states with unique binding signatures; water plays a major role in PF429242 dissociation from the catalytic site. Communication between key catalytic triad residues is altered in the presence of PF429242. In apo-S1P state, S414-S307/V216-D218 is the preferred route but in PF429242-bound state, S414-S417/V216-D218 is preferred. Communication between S414 and H249 is also shortened in PF429242 bound state; here, only L410 is required unlike apo-state, which requires P418, V256 and F252. Ligand binding did not alter the communication route between S414 and H249 as both recruited D244 and G220. In conclusion, PF429242 binds tightly but reversible to S1P and the details of this interaction has been presented to guide future efforts at developing novel inhibitors. Site-1-protease; PF429242; Kon/Koff; Network analysis.
膜结合转录因子位点1蛋白酶（S1P）因其在脂肪生成、溶酶体生物发生、未折叠蛋白反应和病毒糖蛋白加工中的作用，正成为一个新兴的临床靶点。在本研究中，构建了S1P的同源模型，以便通过分子对接、分子动力学模拟和计算机动力学研究来理解PF429242抑制S1P的结构基础。PF429242对接（GlideScore=-5.20 kcal/mol）到催化三联体（D218、H249和S414）中并得到验证（R=0.5686）。可逆结合动力学参数（K/K）估计为7.28E- M，完全结合态和无配体状态之间穿插着3个具有独特结合特征的瞬时配体结合状态；水在PF429242从催化位点解离中起主要作用。在PF429242存在的情况下，关键催化三联体残基之间的通讯发生改变。在无配体S1P状态下，S414-S307/V216-D218是首选途径，但在PF429242结合状态下，S414-S417/V216-D218是首选途径。在PF429242结合状态下，S414和H249之间的通讯也缩短了；在这里，与无配体状态不同，无配体状态需要P418、V256和F252，而这里只需要L410。配体结合并未改变S414和H249之间的通讯途径，因为两者都招募了D244和G220。总之，PF429242与S1P紧密但可逆地结合，并且已经展示了这种相互作用的细节，以指导未来开发新型抑制剂的工作。位点1蛋白酶；PF429242；结合/解离常数；网络分析。
