Student Research Committee, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.
Department of Medicinal Chemistry, School of Pharmacy, Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran.
Mult Scler Relat Disord. 2023 May;73:104622. doi: 10.1016/j.msard.2023.104622. Epub 2023 Mar 16.
Multiple sclerosis (MS) is an autoimmune neurodegenerative disease affecting numerous people worldwide. While the relapsing subtypes of MS are to some extent treatable, the disease remains incurable leading to progressive disability. Limited efficacy of current small molecule drugs necessitates development of efficient and safe MS medications. Accordingly, drug repurposing is an invaluable strategy that recognizes new targets for known drugs especially in the field of poorly addressed therapeutic areas. Drug discovery largely depends on the identification of potential binding molecules to the intended biomolecular target(s). In this regard, current study was devoted to in silico repurposing of 263 small molecule CNS drugs to achieve superior binders to some MS-related targets. On the basis of molecular docking scores, thioxanthene and benzisothiazole-based antipsychotics could be identified as potential binders to sphingosine-1-phosphate lyase (S1PL) and cyclophilin D (CypD). Tightest interaction modes were observed for zuclopenthixol-S1PL (ΔG -7.96 kcal/mol) and lurasidone-CypD (ΔG -8.84 kcal/mol) complexes. Molecular dynamics (MD) simulations proved the appropriate and stable accommodation of top-ranked drugs inside enzyme binding sites during 100 ns. Hydroxyethyl piperazine of zuclopenthixol and benzisothiazole of lurasidone flipped inside the binding pocket to interact with adjacent polar and apolar residues. Solvent accessible surface area (SASA) fluctuations confirmed the results of binding trajectory analysis and showed that non-polar hydrophobic interactions played significant roles in acquired stabilities. Our results on lurasidone binding pattern were interestingly in accordance with previous reports on X-ray structures of other norbornane maleimide derivatives as CypD inhibitors. According to this, Asn144, Phe102 and Phe155 served as important residues in providing stable binding pose of lurasidone through both exo and endo conformations. Although experimental results are necessary to be achieved, the outcomes of this study proposed the potentiality of some thioxanthene and benzisothiazole-based antipsychotics for binding to S1PL and CypD, respectively, as MS-related targets.
多发性硬化症（MS）是一种影响全球众多人群的自身免疫性神经退行性疾病。虽然 MS 的复发亚型在一定程度上是可治疗的，但该疾病仍然无法治愈，导致进行性残疾。目前小分子药物的疗效有限，因此需要开发有效和安全的多发性硬化症药物。因此，药物再利用是一种宝贵的策略，它可以识别已知药物的新靶点，特别是在治疗效果较差的领域。药物发现在很大程度上取决于识别潜在的与预期生物分子靶标结合的分子。在这方面，本研究致力于通过计算机重新利用 263 种小分子中枢神经系统药物，以获得对一些 MS 相关靶标的更好结合物。基于分子对接评分，可以鉴定噻吨和苯并异噻唑类抗精神病药是神经鞘氨醇-1-磷酸裂解酶（S1PL）和亲环蛋白 D（CypD）的潜在结合物。与 zuclopenthixol-S1PL（ΔG-7.96 kcal/mol）和 lurasidone-CypD（ΔG-8.84 kcal/mol）复合物的最紧密相互作用模式。分子动力学（MD）模拟证明了在 100 ns 内，排名靠前的药物能够在酶结合位点内适当且稳定地容纳。zuclopenthixol 的羟乙基哌嗪和 lurasidone 的苯并异噻唑在结合口袋内翻转，与相邻的极性和非极性残基相互作用。溶剂可及表面积（SASA）波动证实了结合轨迹分析的结果，并表明非极性疏水相互作用在获得稳定性方面发挥了重要作用。我们关于 lurasidone 结合模式的结果与以前关于其他降冰片烷马来酰亚胺衍生物作为 CypD 抑制剂的 X 射线结构的报告非常吻合。据此，Asn144、Phe102 和 Phe155 作为重要残基，通过外消旋和内消旋构象为 lurasidone 提供稳定的结合构象。尽管需要进行实验验证，但本研究的结果表明，一些噻吨和苯并异噻唑类抗精神病药有可能分别作为 MS 相关靶标与 S1PL 和 CypD 结合。
