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首页> 外文期刊>Open Pharmaceutical Sciences Journal >Computational Studies on Imidazo[1,2-a] Pyridine-3-Carboxamide Analogues as Antimycobacterial Agents: Common Pharmacophore Generation, Atom-based 3D-QSAR, Molecular dynamics Simulation, QikProp, Molecular Docking and Prime MMGBSA Approaches
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Computational Studies on Imidazo[1,2-a] Pyridine-3-Carboxamide Analogues as Antimycobacterial Agents: Common Pharmacophore Generation, Atom-based 3D-QSAR, Molecular dynamics Simulation, QikProp, Molecular Docking and Prime MMGBSA Approaches

机译：咪唑并[1,2-a]吡啶-3-羧酰胺类似物作为抗分枝杆菌剂的计算研究：常见药效基团，基于原子的3D-QSAR，分子动力学模拟，QikProp，分子对接和主要MMGBSA方法

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Background:IMB-1402, Q203 and ND09759 analogs were found to have strong efficiency against Multi-drug-resistant tuberculosis (MDR-TB)/Extensively drug-resistant tuberculosis (XDR-TB) strains.Objectives:To know the structural necessities for imidazo[1,2-a]pyridine-3-carboxamide analogues, we intended to develop the ligand-based pharmacophore, Quantitative structure–activity relationship models(3D-QSAR model). We also performed Molecular docking, molecular simulation and Prime/Molecular Mechanics Generalized Born Surface Area (Prime/MM-GBSA) studies.Methods:All the studies like Common pharmacophore hypothesis generation, Atom based 3D-QSAR study, Prime MMGBSA, Docking, Qikprop, and Molecular dynamics simulation were processed using various modules incorporated within the maestro software interface from Schrodinger, LLC, New York USA (release 2017).Results:The common pharmacophore hypothesis(CPH) generation resulted in a five-featured hypothesis HHPRR, containing 1 positive, 2 hydrophobic and 2 aromatic rings. An Atom-based 3D-QSAR model was predicted for twenty seven training sets (a correlation coefficient i.e. R~(2)= 0.9181,Standard deviation i.e. SD =0.3305, variance ratio i.e. F = 85.9) and eleven test sets (cross-validation correlation coefficient i.e. Q~(2) =0.6745, Root Mean Square Error i.e. RMSE = 0.65, Pearson R = 0.8427, P=1.21E-12) compounds employing alignment based on CPH. The dataset of thirty-eight molecules was allowed for docking into the active site of pantothenate synthetase (PDBID-3IVX) that shows H-bonding (Hydrogen bonding) interactions with residues Gly158, Met195, Pro38 and additionally shows further Pi-cation interactions with a residue like Hie47. We also obtained good simulation results for1.2ns study.Conclusion:From the results, the generated 3D-QSAR model may be applicable for additional designing of various novel potent derivatives in the future.
机译：背景：发现IMB-1402，Q203和ND09759类似物对耐多药结核病（MDR-TB）/广泛耐药结核病（XDR-TB）菌株具有强效。目的：了解咪唑的结构必要性[1,2-a]吡啶-3-羧酰胺类似物，我们打算开发基于配体的药效团，定量构效关系模型（3D-QSAR模型）。我们还进行了分子对接，分子模拟和质子/分子力学广义生表面积（Prime / MM-GBSA）研究。方法：所有研究，如通用药效团假设生成，基于Atom的3D-QSAR研究，质子MMGBSA，对接，Qikprop ，并使用美国纽约Schrodinger，LLC（2017年发行）的maestro软件界面中包含的各种模块处理了分子动力学模拟。结果：通用药效基团假说（CPH）的产生导致五特征假说HHPRR，其中包含1正，2个疏水和2个芳香环。预测了27个训练集的基于Atom的3D-QSAR模型（​​相关系数即R〜（2）= 0.9181，标准偏差即SD = 0.3305，方差比即F = 85.9 ）和11个测试集（交叉验证相关系数即Q〜（2）= 0.6745，均方根误差即RMSE = 0.65，皮尔森R = 0.8427，P = 1.21E-12））基于CPH。允许38个分子的数据集对接入泛酸合成酶（PDBID-3IVX）的活性位点，该活性位点显示与残基Gly158，Met195，Pro38的H键（氢键）相互作用，另外还显示与Ply的进一步Pi-阳离子相互作用残留像Hie47。在1.2ns的研究中，我们也获得了良好的仿真结果。结论：从结果来看，所生成的3D-QSAR模型将来可能适用于各种新型有效衍生物的额外设计。

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