左氧氟沙星结构衍生物与细菌 IIA 型拓扑异构酶活性受体位点结合机制的硅学活性预测和对接研究

IF 2.3 Q3 PHARMACOLOGY & PHARMACY
E. Uspenskaya, Vasilisa A. Sukhanova, Ekaterina S. Kuzmina, T. Pleteneva, Olga V. Levitskaya, Timur M. Garaev, Anton V. Syroeshkin
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引用次数: 0

摘要

微生物对抗生素的持久耐药性以及大流行病的日益频繁,都促使人们需要新的抗菌剂(AntAg)。由于 AntAg 的缺乏,旨在开发快速方法寻找新候选药物的研究具有现实意义。本研究旨在对四种结构不同的左氧氟沙星(Lvf)与细菌拓扑异构酶 IIA 型靶标(DNA 回旋酶和拓扑异构酶 IV)的生物活性谱和分子结合机制进行硅学研究,以便开发出具有更好安全性特征的药物。为实现这一目标,使用了许多软件产品,如 ChemicPen v. 2.6、PyMol 2.5、Avogadro 1.2.0、PASS、AutoDockTools 1.5.7 和新一代软件 Autodock Vina。这些软件产品是首批可用于确定配体-受体配对结合亲和力、聚类坐标和拟议作用机制的可视化聚类软件。Lvf 是一种脱羧衍生物,其真实结构之一是通过摩擦生化(TrbCh)暴露获得的。分子配体的作用谱是根据贝叶斯概率活性预测模型(PASS 软件 2.0 版)描述的。通过 Wiener (W)、Balaban (Vs)、Detour (Ip) 和 Electropy € 指数将 Lvf 的预测分子结构和真实分子结构(PMS 和 RMS)转化为描述符,结构复杂程度依次降低。二维 "结构-活性 "图用于区分左氧氟沙星的密切相关结构。PMS 和 RMS 被视为配体-受体复合物的三维模型。展示了 RMS 和 PMS 与关键氨基酸残基--SER-79、DT-15、DG-1、DA-1 的接触区域。此外,还给出了分子内和分子间的结合位点、自由能数据(亲和力值,kcal/mol)、结合常数 Kb(M-1)和簇数。所介绍的硅学方法可用于探索药物的作用谱,找到定量的 "结构-活性 "相关性,并预测分子机理。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In Silico Activity Prediction and Docking Studies of the Binding Mechanisms of Levofloxacin Structure Derivatives to Active Receptor Sites of Bacterial Type IIA Topoisomerases
The need for new antimicrobial agents (AntAg) is driven by the persistent antibiotic resistance in microorganisms, as well as the increasing frequency of pandemics. Due to the deficiency of AntAg, research aimed at developing speedy approaches to find new drug candidates is relevant. This study aims to conduct an in silico study of the biological activity spectrum as well as the molecular binding mechanisms of four structurally different forms of levofloxacin (Lvf) with bacterial topoisomerases targets of type IIA (DNA gyrase and topoisomerase IV) to enable the development of drugs with an improved characterization of the safety profile. To achieve this goal, a number of software products were used, such as ChemicPen v. 2.6, PyMol 2.5, Avogadro 1.2.0, PASS, AutoDockTools 1.5.7 with the new generation software Autodock Vina. These software products are the first to be made available for visualization of clusters with determination of ligand-receptor pair binding affinity, as well as clustering coordinates and proposed mechanisms of action. One of the real structures of Lvf, a decarboxylated derivative, was obtained with tribochemical (TrbCh) exposure. The action spectrum of molecular ligands is described based on a Bayesian probability activity prediction model (PASS software Version 2.0). Predicted and real (PMS and RMS) molecular structures of Lvf, with decreasing levels of structural complexity, were translated into descriptors via Wiener (W), Balaban (Vs), Detour (Ip), and Electropy € indices. The 2D «structure-activity» diagrams were used to differentiate closely related structures of levofloxacin. PMS and RMS were visualized as 3D models of the ligand-receptor complexes. The contact regions of RMS and PMS with key amino acid residues—SER-79, DT-15, DG-1, DA-1—were demonstrated. The intra- and inter-molecular binding sites, data on free energy (affinity values, kcal/mol), the binding constant Kb (M−1), and the number of clusters are presented. The research results obtained from the presented in silico approach to explore the spectrum of action find quantitative “structure-activity” correlations, and predict molecular mechanisms may be of applied interest for directed drug discovery.
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来源期刊
Scientia Pharmaceutica
Scientia Pharmaceutica Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
4.60
自引率
4.00%
发文量
67
审稿时长
10 weeks
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