Thermodynamics of binding of angiotensin-converting enzyme inhibitors to enzyme active site model

Šramko, Martin; Garaj, Vladimír; Remko, Milan

doi:10.1016/j.theochem.2008.08.018

Cited by 9 publications

(1 citation statement)

References 67 publications

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“…Despite the rapid accumulation of structural and kinetic data, however, there have been few computational studies on this important system. An earlier density functional theory study focused on a truncated active-site model, while more recent ones investigated docking of various small molecule inhibitors to ACE. , These studies provided no dynamical information concerning the fluctuation of the enzymatic system. A recent molecular dynamics study on an enzyme–substrate complex has been reported by Papakyriakou et al, using a modified Amber force field.…”

Section: Introductionmentioning

confidence: 99%

Inhibitor and Substrate Binding by Angiotensin-Converting Enzyme: Quantum Mechanical/Molecular Mechanical Molecular Dynamics Studies

Wang

et al. 2011

J. Chem. Inf. Model.

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Angiotensin-converting enzyme (ACE) is an important zinc-dependent hydrolase responsible for converting the inactive angiotensin I to the vasoconstrictor angiotensin II and for inactivating the vasodilator bradykinin. However, the substrate binding mode of ACE has not been completely understood. In this work, we propose a model for an ACE Michaelis complex based on two known X-ray structures of inhibitor-enzyme complexes. Specifically, the human testis angiotensin-converting enzyme (tACE) complexed with two clinic drugs were first investigated using a combined quantum mechanical and molecular mechanical (QM/MM) approach. The structural parameters obtained from the 550 ps molecular dynamics simulations are in excellent agreement with the X-ray structures, validating the QM/MM approach. Based on these structures, a model for the Michaelis complex was proposed and simulated using the same computational protocol. Implications to ACE catalysis are discussed.

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Section: Introductionmentioning

confidence: 99%

Inhibitor and Substrate Binding by Angiotensin-Converting Enzyme: Quantum Mechanical/Molecular Mechanical Molecular Dynamics Studies

Wang

et al. 2011

J. Chem. Inf. Model.

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QM/MM Studies on Enzyme Catalysis and Insight into Designing of New Inhibitors by ONIOM Approach: Recent Update

et al. 2023

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Computational enzymology is a rapidly developing area that uniquely provides deep insight into the fundamental processes of biological catalysis at the atomic level. Such in‐depth insight can ultimately be employed in designing potential inhibitors against the targets of interest. Computational enzymology covers a wide range of in‐silico approaches for investigating the enzyme‐catalyzed reaction mechanisms, among which combined quantum mechanics (QM) /molecular mechanics (MM) approaches have gained a lot of attention nowadays. This advanced approach generally involves a QM method (i. e. a method that estimates the electronic structure of the active site) and a simpler MM method (a method that includes the enzyme environment) to understand the enzymatic reactions. The QM/MM method has been widely tested in understanding the molecular mechanisms both at the structural and energetic levels and observed to best correlate with experimental studies of the enzymatic mechanism. It proposes a new mechanism that ultimately opens a new route for designing new potent, efficacious enzyme inhibitors. This review mainly covers wide applications of the ONIOM (Our own N‐layer Integrated molecular Orbital Molecular mechanics) method for decoding the enzymatic catalysis mechanism or designing potential small molecule inhibitors as treatment therapeutics in terms of free energy profiles. Moreover, this article also highlights employing QM/MM method in comprehending the mechanisms for drug metabolism and resistance (owing to mutations). This write‐up may encourage medicinal chemists and molecular biologists to explore this approach to propose more promising therapeutics to improve the quality of treatment.

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Density Functional Theory Calculations of Enzyme–Inhibitor Interactions in Medicinal Chemistry and Drug Design

Rozhenko

2014

Challenges and Advances in Computational Chemistry and Physics

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Thermodynamics of binding of angiotensin-converting enzyme inhibitors to enzyme active site model

Cited by 9 publications

References 67 publications

Inhibitor and Substrate Binding by Angiotensin-Converting Enzyme: Quantum Mechanical/Molecular Mechanical Molecular Dynamics Studies

Inhibitor and Substrate Binding by Angiotensin-Converting Enzyme: Quantum Mechanical/Molecular Mechanical Molecular Dynamics Studies

QM/MM Studies on Enzyme Catalysis and Insight into Designing of New Inhibitors by ONIOM Approach: Recent Update

Density Functional Theory Calculations of Enzyme–Inhibitor Interactions in Medicinal Chemistry and Drug Design

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