Evaluation of novel HIV-1 protease inhibitors with DRV-resistance by utilizing 3D-QSAR molecular docking and molecular dynamics simulation

Zhang, Yanjun; Chen, Lu; Xu, Jie; Jiang, Hui-Fang; Zhu, Yi-Ren; Wang, Zhonghua; Xiong, Fei

doi:10.1039/d2nj04492g

Cited by 10 publications

(7 citation statements)

References 32 publications

(33 reference statements)

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“…Finally, the original ligand small molecule was removed to form the docking active site, and all water molecules were eliminated. The remaining parameters were kept at their default values [31] . The indole‐2‐one class small molecule compounds were docked into the active site of the processed target protein using the SurflexDock Geom mode.…”

Section: Methodsmentioning

confidence: 99%

“…The remaining parameters were kept at their default values. [31] The indole-2-one class small molecule compounds were docked into the active site of the processed target protein using the SurflexDock Geom mode. The non-bonded interactions between the small molecule ligands and the key amino acid residues in the active site were analyzed.…”

Section: Molecular Dockingmentioning

confidence: 99%

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Design of New Second‐Generation TRK Inhibitors Targeting Tropomyosin Receptor Kinases by Using Molecular Docking, Molecular Dynamics Simulations and ADMET Properties

Zhao,

Cui,

Tang

et al. 2024

ChemistrySelect

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TRK, as a type of cell surface protein, plays a critical role in various biological processes, particularly as a key target for cancer treatment. We explored the correlation between the structure and activity of indole‐2‐one derivatives through investigations involving 3D‐QSAR molecular modelling, molecular docking, molecular dynamics, and ADMET property research. The statistical data from the CoMFA and CoMSIA models exhibit excellent internal stability (CoMFA: q2=0.622, r2=0.992; CoMSIA: q2=0.740, r2=0.972). Further molecular docking unveiled the interaction mechanism between small molecules and receptor proteins, demonstrating that the hydrogen bonding between amino acids Met590 and Glu592 and small molecules could enhance the ligand‐receptor binding affinity. Based on the 3D‐QSAR model and molecular docking, we designed and predicted the activity of eight new molecules, which displayed high expected activity. Subsequently, through 100 ns MD simulations and binding free energy calculations, we affirmed the stability of the molecular docking results. Finally, we employed ADMET to predict the pharmacokinetic properties of the newly designed molecules, validating their commendable drug‐like characteristics. These research findings provide valuable references for the design and development of novel TRK inhibitors, offering fresh perspectives for subsequent drug design.

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Section: Methodsmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

Design of New Second‐Generation TRK Inhibitors Targeting Tropomyosin Receptor Kinases by Using Molecular Docking, Molecular Dynamics Simulations and ADMET Properties

Zhao,

Cui,

Tang

et al. 2024

ChemistrySelect

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show abstract

“…To determine the strength of the interaction between the target protein and inhibitors, we used molecular mechanics Poisson‐Boltzmann surface area (MM/PBSA) in conjunction with APBS 3.0 software to calculate the binding free energy (Δ G bind ) for the last 15 ns of the equilibrium trajectory. All the above calculations were done using GROMACS 2020.6 software [35] …”

Section: Methodsmentioning

confidence: 99%

Drug Design, Molecular Docking and Molecular Dynamics Simulations of Indole Class HIV‐1 NNRTIs Explored with QSAR and Topomer Search

et al. 2023

Self Cite

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HIV reverse transcriptase (RT) as one of the key targets for the treatment of HIV, and in recent years a series of indole class non‐nucleoside reverse transcriptase inhibitors (NNRTIs) with potent anti‐HIV‐1 properties have been reported. In this paper, Topomer CoMFA model with reliable validation results (q2=0.809, R2=0.983, R2pred=0.870) for exploring the quantitative structure‐activity relationship (QSAR) of the inhibitors. And the relationship between molecular structures and activities were further analysed using the contour plots. The Topomer search technique was employed to search and then designed novel compounds with stronger inhibitory effects. Molecular docking showed that the residue LYS101, GLU138 and ILE180 played a key role, meanwhile, the stability of the docking results was verified by molecular dynamics simulations (MD). Finally, the calculated results of the binding free energy calculations agree with the predictions of the model, further validating the reliability of the proposed model.

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“…In this research, we employed the ADMET Lab 2.0 and pkCSM online tools to predict the pharmacokinetic properties of our designed compounds. [31][32][33] Our overarching aim is to boost the success rate of drug discovery and thereby alleviate development costs.…”

Section: Admetmentioning

confidence: 99%

Exploring the Efficacy of Noncovalent SARS‐CoV‐2 Main Protease Inhibitors: A Computational Simulation Analysis Study

Xiong,

Zhang,

Jiang

et al. 2024

Chemistry & Biodiversity

Self Cite

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The SARS‐CoV‐2 main protease, as a key target for antiviral therapeutics, is instrumental in maintaining virus stability, facilitating translation, and enabling the virus to evade innate immunity. Our research focused on designing non‐covalent inhibitors to counteract the action of this protease. Utilizing a 3D‐QSAR model and contour map, we successfully engineered eight novel non‐covalent inhibitors. Further evaluation and comparison of these novel compounds through methodologies including molecular docking, ADMET analysis, frontier molecular orbital studies, molecular dynamics simulations, and binding free energy revealed that the inhibitors N02 and N03 demonstrated superior research performance (N02 ΔGbind = ‐206.648 kJ/mol, N03 ΔGbind = ‐185.602 kJ/mol). These findings offer insightful guidance for the further refinement of molecular structures and the development of more efficacious inhibitors. Consequently, future investigations can draw upon these findings to unearth more potent inhibitors, thereby amplifying their impact in the treatment and prevention of associated diseases.

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Evaluation of novel HIV-1 protease inhibitors with DRV-resistance by utilizing 3D-QSAR molecular docking and molecular dynamics simulation

Abstract: HIV-1 protease is a key enzyme in the maturation process of HIV protein. HIV-1 PIs is an important class of drug to inhibit HIV infection and has an important effect...

Cited by 10 publications

References 32 publications

Design of New Second‐Generation TRK Inhibitors Targeting Tropomyosin Receptor Kinases by Using Molecular Docking, Molecular Dynamics Simulations and ADMET Properties

Design of New Second‐Generation TRK Inhibitors Targeting Tropomyosin Receptor Kinases by Using Molecular Docking, Molecular Dynamics Simulations and ADMET Properties

Drug Design, Molecular Docking and Molecular Dynamics Simulations of Indole Class HIV‐1 NNRTIs Explored with QSAR and Topomer Search

Exploring the Efficacy of Noncovalent SARS‐CoV‐2 Main Protease Inhibitors: A Computational Simulation Analysis Study

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