The Increasing Role of QM/MM in Drug Discovery

Lodola, Alessio; Vivo, Marco De

doi:10.1016/b978-0-12-398312-1.00011-1

Cited by 58 publications

(41 citation statements)

References 90 publications

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“…Thus, the quantum mechanics/molecular mechanics (QM/MM) method has been proposed to extend the applicability of FFs to study catalytic mechanisms in drug discovery. 33 In addition, the charge polarizability is disallowed in the traditional FFs over the entire simulation, thus potentially affecting the accuracy of predictions of energetic profiles. 34 Several efforts devoted to achieving electronic redistribution have been coupled to polarizable FFs.…”

Section: Theoretical Backgroundmentioning

confidence: 99%

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

Zheng

Zhao

Chen

et al. 2018

Medicinal Research Reviews

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Over the past quarter of a century, there has been rapid development in structural biology, which now can provide solid evidence for understanding the functions of proteins. Concurrently, computational approaches with particular relevance to the chemical biology and drug design (CBDD) field have also incrementally and steadily improved. Today, these methods help elucidate detailed working mechanisms and accelerate the discovery of new chemical modulators of proteins. In recent years, integrating computational simulations and predictions with experimental validation has allowed for more effective explorations of the structure, function and modulation of important therapeutic targets. In this review, we summarize the main advancements in computational methodology development, which are then illustrated by several successful applications in CBDD. Finally, we conclude with a discussion of the current major challenges and future directions in the field.

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Section: Theoretical Backgroundmentioning

confidence: 99%

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

Zheng

Zhao

Chen

et al. 2018

Medicinal Research Reviews

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“…To understand reactivity and specificity of covalent binders to protein targets, and related drug resistance 18 , combined quantum mechanics/molecular mechanics (QM/MM) methods are a highly promising approach. 15,[19][20][21] Acylation of SBLs by β-lactamase inhibitors is likely to occur with the same mechanism as for β-lactam antibiotics such as benzyl-penicillin (Figs. S1).…”

Section: Multiscale Simulations Of Clavulanate Inhibition Identify Thmentioning

confidence: 99%

Multiscale Simulations of Clavulanate Inhibition Identify the Reactive Complex in Class A β-Lactamases and Predict the Efficiency of Inhibition

et al. 2018

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Clavulanate is used as an effective drug in combination with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we perform combined quantum mechanics/molecular mechanics simulations of several covalent complexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as being responsible for inhibition. Further, the obtained free energy barriers discriminate clinically relevant inhibition (TEM-1) from less effective inhibition (KPC-2).

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“…For example, charge transfer effects upon complex formation are inevitably neglected. In this regard, methods based on quantum mechanics (QM) are sometimes used to refine and enrich the MD‐based results in drug design . Scoring then comes into play, with a plethora of constantly evolving functions and methods to predict the binding energy of each compound and rank them accordingly …”

Section: Improved Sampling Of Configuration Space Through Dynamic Docmentioning

confidence: 99%

Recent advances in dynamic docking for drug discovery

Vivo

Cavalli

2017

WIREs Comput Mol Sci

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Molecular docking allows the evaluation of ligand‐target complementarity. This is the crucial first step in small‐molecule drug discovery. Over the last decade, increasing computer power and more efficient molecular dynamics (MD) software have prompted the use of MD for molecular docking. The resulting dynamic docking offers major improvements by (1) taking full account of the structural flexibility of the drug‐target system and (2) allowing the computation of the free energy and kinetics associated with drug binding. Here, we examine the recent advances in dynamic docking, while also considering the challenges and limitations that this powerful approach must overcome to impact fast‐paced drug discovery. WIREs Comput Mol Sci 2017, 7:e1320. doi: 10.1002/wcms.1320 This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Mechanics Software > Molecular Modeling

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The Increasing Role of QM/MM in Drug Discovery

Cited by 58 publications

References 90 publications

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

Multiscale Simulations of Clavulanate Inhibition Identify the Reactive Complex in Class A β-Lactamases and Predict the Efficiency of Inhibition

Recent advances in dynamic docking for drug discovery

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