Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (B.H.U.), Varanasi, 221005 U.P., India.
Department of Chemistry, Uppsala University, SE-751 20 Uppsala, Sweden.
ACS Chem Neurosci. 2023 Feb 15;14(4):749-765. doi: 10.1021/acschemneuro.2c00738. Epub 2023 Feb 7.
Various pharmacoepidemiological investigational studies have indicated that Proton Pump Inhibitors (PPIs) may increase the likelihood of developing Alzheimer's disease (AD) and non-AD related dementias. Previously, we have reported the inhibition of the acetylcholine biosynthesizing enzyme choline acetyltransferase (ChAT) by PPIs, for which omeprazole, lansoprazole, and pantoprazole exhibited IC values of 0.1, 1.5, and 5.3 μM, respectively. In this study we utilize a battery of computational tools to perceive a mechanistic insight into the molecular interaction of PPIs with the ChAT binding pocket that may further help in designing novel ChAT ligands. Various in-silico tools make it possible for us to elucidate the binding interaction, conformational stability, and dynamics of the protein-ligand complexes within a 200 ns time frame. Further, the binding free energies for the PPI-ChAT complexes were explored. The results suggest that the PPIs exhibit equal or higher binding affinity toward the ChAT catalytic tunnel and are stable throughout the simulated time and that the pyridine ring of the PPIs interacts primarily with the catalytic residue His. A free energy landscape analysis showed that the folding process was linear, and the residue interaction network analysis can provide insight into the roles of various amino acid residues in stabilization of the PPIs in the ChAT binding pocket. As a major factor for the onset of Alzheimer's disease is linked to cholinergic dysfunction, our previous and the present findings give clear insight into the PPI interaction with ChAT. The scaffold can be further simplified to develop novel ChAT ligands, which can also be used as ChAT tracer probes for the diagnosis of cholinergic dysfunction and to initiate timely therapeutic interventions to prevent or delay the progression of AD.
各种药物流行病学研究表明，质子泵抑制剂（PPIs）可能会增加患阿尔茨海默病（AD）和非 AD 相关痴呆的可能性。之前，我们已经报道了 PPIs 抑制乙酰胆碱生物合成酶胆碱乙酰转移酶（ChAT）的作用，其中奥美拉唑、兰索拉唑和泮托拉唑的 IC 值分别为 0.1、1.5 和 5.3 μM。在这项研究中，我们利用一系列计算工具来了解 PPI 与 ChAT 结合口袋的分子相互作用的机制，这可能有助于设计新型的 ChAT 配体。各种计算工具使我们能够阐明在 200 ns 时间范围内的蛋白质-配体复合物的结合相互作用、构象稳定性和动力学。此外，还研究了 PPI-ChAT 复合物的结合自由能。结果表明，PPIs 对 ChAT 催化隧道表现出同等或更高的结合亲和力，并且在整个模拟时间内都是稳定的，PPIs 的吡啶环主要与催化残基 His 相互作用。自由能景观分析表明，折叠过程是线性的，残基相互作用网络分析可以深入了解各种氨基酸残基在稳定 PPI 进入 ChAT 结合口袋中的作用。由于阿尔茨海默病的发病主要与胆碱能功能障碍有关，我们之前和现在的研究结果清楚地揭示了 PPI 与 ChAT 的相互作用。该支架可以进一步简化，以开发新型的 ChAT 配体，也可以作为 ChAT 示踪探针用于诊断胆碱能功能障碍，并及时进行治疗干预，以预防或延缓 AD 的进展。
