Shamsi Anas, Shahwan Moyad, Zuberi Azna, Altwaijry Nojood
Center for Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab Emirates.
College of Pharmacy and Health Sciences, Ajman University, Ajman 346, United Arab Emirates.
Pharmaceuticals (Basel). 2024 Nov 15;17(11):1536. doi: 10.3390/ph17111536.
Histone deacetylase 6 (HDAC6) plays a crucial role in neurological, inflammatory, and other diseases; thus, it has emerged as an important target for therapeutic intervention. To date, there are no FDA-approved HDAC6-targeting drugs, and most pipeline candidates suffer from poor target engagement, inadequate brain penetration, and low tolerability. There are a few HDAC6 clinical candidates for the treatment of mostly non-CNS cancers as their pharmacokinetic liabilities exclude them from targeting HDAC6-implicated neurological diseases, urging development to address these challenges. They also demonstrate off-target toxicity due to limited selectivity, leading to adverse effects in patients. Selective inhibitors have thus been the focus of development over the past decade, though no selective and potent HDAC6 inhibitor has yet been approved.
This study involved an integrated virtual screening against HDAC6 using the DrugBank database to identify repurposed drugs capable of inhibiting HDAC6 activity. The primary assessment involved the determination of the ability of molecules to bind with HDAC6. Subsequently, interaction analyses and 500 ns molecular dynamics (MD) simulations followed by essential dynamics were carried out to study the conformational flexibility and stability of HDAC6 in the presence of the screened molecules, i.e., penfluridol and pimozide.
The virtual screening results pinpointed penfluridol and pimozide as potential repurposed drugs against HDAC6 based on their binding efficiency and appropriate drug profiles. The docking results indicate that penfluridol and pimozide share the same binding site as the reference inhibitor with HDAC6. The MD simulation results showed that stable protein-ligand complexes of penfluridol and pimozide with HDAC6 were formed. Additionally, MMPBSA analysis revealed favorable binding free energies for all HDAC6-ligand complexes, confirming the stability of their interactions.
The study implies that both penfluridol and pimozide have strong and favorable binding with HDAC6, which supports the idea of repositioning these drugs for the management of neurodegenerative disorders. However, further in-depth studies are needed to explore their efficacy and safety in biological systems.
组蛋白去乙酰化酶6（HDAC6）在神经、炎症及其他疾病中起关键作用；因此，它已成为治疗干预的重要靶点。迄今为止，尚无美国食品药品监督管理局（FDA）批准的靶向HDAC6的药物，大多数处于研发阶段的候选药物存在靶点结合不佳、脑渗透性不足和耐受性低等问题。有少数用于治疗大多数非中枢神经系统癌症的HDAC6临床候选药物，因其药代动力学缺陷使其无法用于治疗与HDAC6相关的神经疾病，这促使开展研发以应对这些挑战。它们还因选择性有限而表现出脱靶毒性，导致患者出现不良反应。因此，在过去十年中，选择性抑制剂一直是研发的重点，不过尚无选择性且强效的HDAC6抑制剂获批。
本研究利用药物银行（DrugBank）数据库对HDAC6进行综合虚拟筛选，以鉴定能够抑制HDAC6活性的 repurposed 药物。初步评估涉及测定分子与HDAC6结合的能力。随后，进行相互作用分析和500纳秒分子动力学（MD）模拟，接着进行主成分动力学分析，以研究在筛选出的分子（即五氟利多和匹莫齐特）存在的情况下HDAC6的构象灵活性和稳定性。
虚拟筛选结果根据五氟利多和匹莫齐特的结合效率及合适的药物特性，确定它们为针对HDAC6的潜在repurposed药物。对接结果表明，五氟利多和匹莫齐特与HDAC6的结合位点与参考抑制剂相同。MD模拟结果显示，五氟利多和匹莫齐特与HDAC6形成了稳定的蛋白质-配体复合物。此外，MMPBSA分析揭示了所有HDAC6-配体复合物具有良好的结合自由能，证实了它们相互作用的稳定性。
该研究表明五氟利多和匹莫齐特与HDAC6均具有强烈且良好的结合，这支持了将这些药物重新用于治疗神经退行性疾病的想法。然而，需要进一步深入研究以探索它们在生物系统中的疗效和安全性。
