Uzma Saqib, Isaac S Demaree, Alexander G Obukhov, Mirza S Baig, Mohd Shahnawaz Khan, Nojood Altwaijry, Mochammad Arfin Fardiansyah Nasution, Kenji Mizuguchi, Krishnan Hajela
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引用次数: 0
Abstract
Transient Receptor Potential Canonical 5 (T RP C5) and T RP C6 channels play critical physiological roles in various cell types. Their involvement in numerous disease progression mechanisms has led to extensive searches for their inhibitors. Although several potent T RP C inhibitors have been developed and the structure of their binding sites were mapped using cryo electron microscopy, a comprehensive understanding of the molecular interactions within the inhibitor binding site of T RP Cs remains elusive. This study aimed to decipher the structural determinants and molecular mechanisms contributing to the differential binding of clemizole to T RP C5 and T RP C6, with a particular focus on the accessibility of binding site residues. This information can help better understand what molecular features allow for selective binding, which is a key characteristic of clinically effective pharmacological agents. Using computational methodologies, we conducted an in-depth molecular docking analysis of clemizole with T RP C5 and T RP C6 channels. The protein structures were retrieved from publicly accessible protein databases. Discovery Studio 2020 Client Visualizer and Chimera software facilitated our in-silico mutation experiments and enabled us to identify the critical structural elements influencing clemizole binding. Our study reveals key molecular determinants at the clemizole binding site, specifically outlining the role of residues' Accessible Surface Area (ASA) and Relative Accessible Surface Area (RASA) in differential binding. We found that lower accessibility of T RP C6 binding site residues, compared to those in T RP C5, could account for the lower affinity binding of clemizole to T RP C6. This work illuminates the pivotal role of binding site residue accessibility in determining the affinity of clemizole to T RP C5 and T RP C6. A nuanced understanding of the distinct binding properties between these homologous proteins may pave the way for the development of more selective inhibitors, promising improved therapeutic efficacy and fewer off-target effects. By demystifying the structural and molecular subtleties of T RP C inhibitors, this research could significantly accelerate the drug discovery process, offering hope to patients afflicted with T RP C-related diseases.
瞬时受体电位典型 5(T RP C5)和 T RP C6 通道在各种细胞类型中发挥着关键的生理作用。由于它们参与了多种疾病的进展机制,人们开始广泛寻找它们的抑制剂。尽管已经开发出了几种强效的 T RP C 抑制剂,并利用低温电子显微镜绘制出了它们的结合位点结构图,但对 T RP Cs 抑制剂结合位点内的分子相互作用的全面了解仍然遥不可及。本研究旨在破译导致氯咪唑与 T RP C5 和 T RP C6 不同结合的结构决定因素和分子机制,尤其关注结合位点残基的可及性。这些信息有助于更好地理解选择性结合的分子特征,而选择性结合是临床有效药剂的一个关键特征。利用计算方法,我们对 clemizole 与 T RP C5 和 T RP C6 通道进行了深入的分子对接分析。蛋白质结构取自可公开访问的蛋白质数据库。Discovery Studio 2020 Client Visualizer 和 Chimera 软件为我们的体内突变实验提供了便利,使我们能够确定影响氯咪唑结合的关键结构元素。我们的研究揭示了氯咪唑结合位点的关键分子决定因素,特别是概述了残基的可及表面积(ASA)和相对可及表面积(RASA)在不同结合中的作用。我们发现,与 T RP C5 中的残基相比,T RP C6 结合位点残基的可及性较低,这可能是氯咪唑与 T RP C6 结合亲和力较低的原因。这项研究揭示了结合位点残基可及性在决定氯咪唑与 T RP C5 和 T RP C6 的亲和力方面的关键作用。对这些同源蛋白之间不同结合特性的细致了解可能会为开发更具选择性的抑制剂铺平道路,从而有望提高疗效并减少脱靶效应。通过揭开 T RP C 抑制剂的结构和分子奥妙的神秘面纱,这项研究可以大大加快药物发现的进程,为饱受 T RP C 相关疾病折磨的患者带来希望。
期刊介绍:
The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.