HEC72702手性对乙型肝炎病毒衣壳二聚体选择性抑制的影响：动

StephenW

Impact of HEC72702 Chirality on the Selective Inhibition of Hepatitis B Virus Capsid Dimer: A Dynamics-Structure-Energetics Perspective
Abdolkarim Farrokhzadeh  1 , Farideh Badichi Akher  2   3 , Fisayo A Olotu  4 , Fanie R Van Heerden  1
Affiliations
Affiliations

    1
    School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Pietermaritzburg, 3209, South Africa.
    2
    Department of Computer Science, University of Cape Town, Cape Town, South Africa.
    3
    Department of Chemistry, University of Cape Town, Cape Town, 7707, South Africa.
    4
    Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.

    PMID: 32757484 DOI: 10.1111/cbdd.13771

Abstract

Chirality in drug design has been attracting wide interests and attention over the years based on its innate potentials of enhancing the selectivity and prowess of therapeutic molecules. This approach was fundamental to the recent design of two inhibitors, where (R,R)-HEC72702 exhibited higher potency inhibition against hepatitis B virus capsid (HBVC) than (R,S)-HEC72702. Nevertheless, the detailed molecular mechanism has remained unresolved. Here, we apply multiple computational approaches to explore, validate, and differentiate the binding modes of (R,R) and (R,S)-HEC72702 and to explain the systematic roles mediated by chirality on the distinctive inhibition of HBVC dimer (HBVCd). Our findings revealed that chirality change from R,S to R,R engenders variations in the position of the propanoic acid group of HEC72702 towards the α5' and C-TER' region of HBVCd chain B which could explain the higher inhibitory affinity of (R,R)-HEC72702. Estimated binding free energies revealed a good correlation with bioactivity data. Moreover, analysis of energy decomposition revealed the prominent effects of van der Waals interactions in the binding process of both compounds to HBVCd. Furthermore, hierarchical clustering of residue-based energetic contributions suggested two hot-spot residues W125´ and F156´ play crucial roles in the systematic motions of the propanoic acid group towards chain B.

Keywords: Chirality; Hepatitis B virus capsid dimer (HBVCd); Inhibitor; MD simulation.

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StephenW

HEC72702手性对乙型肝炎病毒衣壳二聚体选择性抑制的影响：动力学-结构-能量学的角度
Abdolkarim Farrokhzadeh 1，Farideh Badichi Akher 2 3，Fisayo A Olotu 4，Fanie R Van Heerden 1
隶属关系
隶属关系

    1个
    夸祖鲁-纳塔尔大学化学与物理学院，专用袋X01，皮特马里茨堡，3209，南非。
    2
    南非开普敦开普敦大学计算机科学系。
    3
    南非开普敦开普敦大学化学系，南非7707。
    4
    夸祖鲁-纳塔尔大学卫生科学学院分子生物计算和药物设计实验室，南非德班，韦斯特维尔校区，4001。

    PMID：32757484 DOI：10.1111 / cbdd.13771

抽象

多年来，药物设计中的手性因其固有的提高治疗分子的选择性和能力的先天潜力而引起了广泛的关注和关注。这种方法是最近设计两种抑制剂的基础，其中（R，R）-HEC72702对乙型肝炎病毒衣壳（HBVC）的抑制作用比（R，S）-HEC72702高。然而，详细的分子机制仍未解决。在这里，我们应用多种计算方法来探索，验证和区分（R，R）和（R，S）-HEC72702的结合模式，并解释由手性介导的对HBVC二聚体（HBVCd）的独特抑制的系统作用。我们的发现表明，从R，S到R，R的手性变化导致HEC72702的丙酸基团向HBVCd链B的α5'和C-TER'区域的位置变化，这可能解释了（R ，R）-HEC72702。估计的结合自由能显示出与生物活性数据的良好相关性。此外，能量分解分析揭示了范德华相互作用在两种化合物与HBVCd结合过程中的显着影响。此外，基于残基的能量贡献的层次聚类表明，两个热点残基W125'和F156'在丙酸基团向链B的系统运动中起关键作用。

关键词：手性；乙型肝炎病毒衣壳二聚体（HBVCd）;抑制剂MD模拟。

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