基于结构的FDA批准药物的筛选鉴定了潜在的组蛋白脱乙酰基酶3重新利用的抑制剂：分子对接和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
影响因子:4.80000
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
摘要
组蛋白脱乙酰基酶3（HDAC3）是组蛋白脱乙酰基酶家族的成员，它已成为寻求针对各种复杂疾病（包括癌症）的新型治疗干预措施的关键靶标。 FDA批准的药物的重新定位为快速发现潜在的HDAC3抑制剂的途径提供了有希望的途径。在这项研究中，我们对从药品银行获得的FDA批准药物进行了基于结构的虚拟筛查。根据其结合亲和力以及与HDAC3的相互作用选择候选命中。然后，对这些有希望的热门人士进行了对其生物学特性和药物谱的全面评估。我们的调查确定了两种经FDA批准的药物，即伊马替尼和腕胺，其特征在于它们对HDAC3的结合口袋的特殊性和特异性。这些分子表现出对HDAC3结合位点的强烈偏爱，并与活性位点袋中功能意义的残基形成了相互作用。为了更深入了解结合动力学，结构稳定性和相互作用机制，我们进行了分子动力学（MD）模拟，跨越了300纳秒（NS）。 MD仿真的结果表明，伊马替尼和腕足是稳定了HDAC3的结构，并引起了较少的构象变化。综上所述，这项研究的发现表明，伊马替尼和腕胺可能为治疗复杂疾病（尤其是癌症）提供了重要的治疗潜力。
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.