A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors.
A multiscale approach to predict the binding mode of metallo beta-lactamase inhibitors.
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DOI：
10.1002/prot.26227
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发表时间：
2022-03
期刊：
影响因子：
2.9
通讯作者：
Mulholland AJ
中科院分区：
文献类型：
--
作者：
Gervasoni S;Spencer J;Hinchliffe P;Pedretti A;Vairoletti F;Mahler G;Mulholland AJ
抗生素耐药性是全球公共卫生的主要威胁。催化β-内酰胺抗生素分解的β-内酰胺酶是主要原因。金属β-内酰胺酶（MBL）代表了一个特殊的挑战，因为它们水解几乎所有的β-内酰胺，迄今为止还没有MBL抑制剂被批准用于临床使用。分子模拟可以帮助药物发现，例如预测抑制剂复合物，但经验分子力学（MM）方法通常对金属蛋白表现不佳。在这里，我们提出了一个多尺度的方法来模拟巯基抑制剂结合IMP-1，一个临床上重要的MBL含有两个催化锌离子，并预测2-巯基甲基噻唑烷（MMTZ）抑制剂的结合模式。首先将抑制剂对接到IMP-1活性位点，测试不同的对接程序和对多种晶体结构的评分功能。然后对复合物进行分子动力学（MD）模拟，随后通过使用密度泛函理论（DFT）方法B3 LYP/6- 31 G（d）的QM/MM优化进行改进，从而通过连续步骤提高方法的准确性。该工作流程在两种IMP-1：MMTZ复合物上进行了测试，其再现了晶体学观察到的结合，并应用于预测第三种MMTZ抑制剂的结合模式，该第三种MMTZ抑制剂的复合物结构在晶体学上难以处理。我们还测试了12-6-4非键相互作用模型在MD模拟和优化与SCC-DFTB QM/MM方法。结果表明，经验模型治疗这些系统的局限性，并表示需要更高层次的计算，如DFT/MM，可靠的结构预测。这项工作证明了一个可靠的计算管道，可应用于MBLs和其他锌金属酶系统的抑制剂设计。
Antibiotic resistance is a major threat to global public health. β-lactamases, which catalyze breakdown of β-lactam antibiotics, are a principal cause. Metallo β-lactamases (MBLs) represent a particular challenge because they hydrolyze almost all β-lactams and to date no MBL inhibitor has been approved for clinical use. Molecular simulations can aid drug discovery, e.g. predicting inhibitor complexes, but empirical molecular mechanics (MM) methods often perform poorly for metalloproteins. Here we present a multiscale approach to model thiol inhibitor binding to IMP-1, a clinically important MBL containing two catalytic zinc ions, and predict the binding mode of a 2-mercaptomethyl thiazolidine (MMTZ) inhibitor. Inhibitors were first docked into the IMP-1 active site, testing different docking programs and scoring functions on multiple crystal structures. Complexes were then subjected to molecular dynamics (MD) simulations and subsequently refined through QM/MM optimization with a density functional theory (DFT) method, B3LYP/6–31G(d), increasing the accuracy of the method with successive steps. This workflow was tested on two IMP-1:MMTZ complexes, for which it reproduced crystallographically observed binding, and applied to predict the binding mode of a third MMTZ inhibitor for which a complex structure was crystallographically intractable. We also tested a 12–6-4 non-bonded interaction model in MD simulations and optimization with a SCC-DFTB QM/MM approach. The results show the limitations of empirical models for treating these systems and indicate the need for higher level calculations, e.g. DFT/MM, for reliable structural predictions. This work demonstrates a reliable computational pipeline that can be applied to inhibitor design for MBLs and other zinc-metalloenzyme systems.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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DOI：
10.1039/c4cp00908h
发表时间：
2014-07-28
期刊：
Physical chemistry chemical physics : PCCP
影响因子：
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作者：
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通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
Shoichet, BK