Using molecular dynamics simulations to evaluate active designs of cephradine hydrolase by molecular mechanics/Poisson–Boltzmann surface area and molecular mechanics/generalized Born surface area methods

Xue, Jing; Huang, Xiaoqiang; Zhu, Yushan

doi:10.1039/c9ra02406a

Cited by 24 publications

(10 citation statements)

References 53 publications

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“…A series of 10 ns trajectories were collected for structural and tunnel analysis. The binding energies were calculated with the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach and three types of the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) approach [39] . The five replicas of molecular dynamics trajectories were extracted every 400 ps, producing a representative ensemble for each enzymesubstrate complex to estimate the binding energies between substrate and protein.…”

Section: Molecular Dynamics Simulation and Calculationmentioning

confidence: 99%

Iterative Alanine Scanning Mutagenesis Confers Aromatic Ketone Specificity and Activity of L‐Amine Dehydrogenases

Mao

et al. 2021

ChemCatChem

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Direct reductive amination of prochiral ketones catalyzed by amine dehydrogenases is attractive in the synthesis of active pharmaceutical ingredients. Here, we report the protein engineering of L-Bacillus cereus amine dehydrogenase to allow reactivity on synthetically useful aromatic ketone substrates using an iterative, multiple-site alanine scanning mutagenesis approach. Mutagenesis libraries based on molecular docking, iterative alanine scanning, and double-proximity filter approach significantly expand the scope of active pharmaceutical ingre-dients relevant building blocks. The eventual quintuple mutant (A115G/T136A/L42A/V296A/V293A) showed reactivity toward aromatic ketones 12 a (5-phenyl-pentan-2-one) and 13 a (6-phenyl-hexan-2-one), which have not been reported to serve as targets of reductive amination by currently available amine dehydrogenases. Docking simulation and tunnel analysis provided valuable insights into the source of the acquired specificity and activity.

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Section: Molecular Dynamics Simulation and Calculationmentioning

confidence: 99%

Iterative Alanine Scanning Mutagenesis Confers Aromatic Ketone Specificity and Activity of L‐Amine Dehydrogenases

Mao

et al. 2021

ChemCatChem

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“…Here, DG binding describes the binding free energy of the protein-drug complexes, DE mm describes the gas phase molecular mechanics energy, DG pol and DG np describes the polar and non-polar solvation energies, respectively. The TDS component denotes the change in entropy at temperature T. Assuming that the NSP15-drug complexes experienced a similar change in conformational entropy, the TDS component was ignored to reduce the computational cost (Xue et al, 2019). The DE mm term can be broken down into two constituting components, namely bonded (bond, angle, dihedral and improper interactions) and non-bonded interactions (van der Waals and electrostatic contributions).…”

Section: Binding Free Energy Calculations Using Mm/pbsamentioning

confidence: 99%

Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: anin silicoassisted drug-repurposing study

Khan

Jha

Singh

et al. 2020

Journal of Biomolecular Structure and Dynamics

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The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (DG), estimated inhibition constants (Ki), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of À259.522 ± 17.579 and À154.051 ± 33.628 kJ/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2.

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“…Evaluation of binding free energies through virtual screening has shown promise in efficiently narrowing the chemical search space for candidate compounds and streamlining the process of lead compound optimization. Outside of the pharmaceutical field, binding affinity predictions find additional uses in protein engineering, and guide the rational design of mutations altering enzyme substrate/product specificity ( Kaushik et al, 2018 ; Li Y. et al, 2019 ; Bhati et al, 2019 ; Ono et al, 2020 ; Chen et al, 2021 ), structural stability ( Aldeghi et al, 2018 ; Jandova et al, 2018 ; Pourjafar-Dehkordi et al, 2019 ; Martin et al, 2020 ), and catalytic efficiency ( Xue et al, 2019 ; Wang K. et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Recent Developments in Free Energy Calculations for Drug Discovery

King

Aitchison

et al. 2021

Front. Mol. Biosci.

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The grand challenge in structure-based drug design is achieving accurate prediction of binding free energies. Molecular dynamics (MD) simulations enable modeling of conformational changes critical to the binding process, leading to calculation of thermodynamic quantities involved in estimation of binding affinities. With recent advancements in computing capability and predictive accuracy, MD based virtual screening has progressed from the domain of theoretical attempts to real application in drug development. Approaches including the Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA), Linear Interaction Energy (LIE), and alchemical methods have been broadly applied to model molecular recognition for drug discovery and lead optimization. Here we review the varied methodology of these approaches, developments enhancing simulation efficiency and reliability, remaining challenges hindering predictive performance, and applications to problems in the fields of medicine and biochemistry.

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Using molecular dynamics simulations to evaluate active designs of cephradine hydrolase by molecular mechanics/Poisson–Boltzmann surface area and molecular mechanics/generalized Born surface area methods

Abstract: A quantitative assessment method for computational enzyme design was developed to rank the active designs of cephradine hydrolase based on molecular dynamics simulation.

Cited by 24 publications

References 53 publications

Iterative Alanine Scanning Mutagenesis Confers Aromatic Ketone Specificity and Activity of L‐Amine Dehydrogenases

Iterative Alanine Scanning Mutagenesis Confers Aromatic Ketone Specificity and Activity of L‐Amine Dehydrogenases

Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: anin silicoassisted drug-repurposing study

Recent Developments in Free Energy Calculations for Drug Discovery

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