基于结构的FDA已批准药物筛选，鉴定潜在的组蛋白脱乙酰酶3（HDAC3）再利用抑制剂：分子对接与分子动力学模拟方法

Structure-based screening of FDA-approved drugs identifies potential histone deacetylase 3 repurposed inhibitor: molecular docking and molecular dynamic simulation approaches

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Frontiers in Pharmacology

影响因子:4.8

分区:医学3区 / 药学3区

发表日期:2024

作者: Anas Shamsi, Mohd Shahnawaz Khan, Dharmendra Kumar Yadav, Moyad Shahwan

DOI: 10.3389/fphar.2024.1424175

摘要

组蛋白去乙酰酶3（HDAC3）是组蛋白去乙酰酶家族的成员，已成为针对多种复杂疾病（包括癌症）寻找新型治疗干预的关键靶点。FDA已批准药物的再定位为快速发现潜在HDAC3抑制剂提供了一条有前景的途径。本研究利用DrugBank中获得的药物进行基于结构的虚拟筛选。根据结合亲和力和与HDAC3的相互作用选择候选药物。筛选结果显示两种药物，伊马替尼（Imatinib）和卡皮普拉嗪（Carpipramine），具有优异的结合亲和力和特异性，能与HDAC3的活性位点形成稳定的相互作用。为了深入理解结合动力学、结构稳定性和作用机制，我们进行了持续300纳秒（ns）的分子动力学（MD）模拟。模拟结果显示，伊马替尼和卡皮普拉嗪稳定了HDAC3的结构，减少了构象变化。综上所述，本研究表明这两种药物可能具有重要的治疗潜力，特别是在癌症等复杂疾病的治疗中。

Abstract

Histone deacetylase 3 (HDAC3) is a member of the histone deacetylase family that has emerged as a crucial target in the quest for novel therapeutic interventions against various complex diseases, including cancer. The repositioning of FDA-approved drugs presents a promising avenue for the rapid discovery of potential HDAC3 inhibitors. In this study, we performed a structure-based virtual screening of FDA-approved drugs obtained from DrugBank. Candidate hits were selected based on their binding affinities and interactions with HDAC3. These promising hits were then subjected to a comprehensive assessment of their biological properties and drug profiles. Our investigation identified two FDA-approved drugs, Imatinib and Carpipramine, characterized by their exceptional affinity and specificity for the binding pocket of HDAC3. These molecules demonstrated a strong preference for HDAC3 binding site and formed interactions with functionally significant residues within the active site pocket. To gain deeper insights into the binding dynamics, structural stability, and interaction mechanisms, we performed molecular dynamics (MD) simulations spanning 300 nanoseconds (ns). The results of MD simulations indicated that Imatinib and Carpipramine stabilized the structure of HDAC3 and induced fewer conformational changes. Taken together, the findings from this study suggest that Imatinib and Carpipramine may offer significant therapeutic potential for treating complex diseases, especially cancer.