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Identification of apigenin-4’-glucoside as bacterial DNA gyrase inhibitor by QSAR modeling, molecular docking, DFT, molecular dynamics, and in vitro confirmation studies

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Abstract

Context

It is well known that antibiotic resistance is a major health hazard. To eradicate antibiotic-resistant bacterial infections, it is essential to find a novel antibacterial agent. Hence, in this study, a quantitative structure–activity relationship (QSAR) model was developed using 43 DNA gyrase inhibitors, and 700 natural compounds were screened for their antibacterial properties. Based on molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies, the top three leads viz., apigenin-4’-glucoside, 8-deoxygartanin, and cryptodorine were selected and structurally optimized using density functional theory (DFT) studies. The optimized structures were redocked, and molecular dynamic (MD) simulations were performed. Binding energies were calculated by molecular mechanics/Poisson–Boltzmann surface area solvation (MM-PBSA). Based on the above studies, apigenin-4’-glucoside was identified as a potent antibacterial lead. Further in vitro confirmation studies were performed using the plant Lawsonia inermis containing apigenin-4’-glucoside to confirm the antibacterial activity.

Methods

For QSAR modeling, 2D descriptors were calculated by PaDEL-Descriptors v2.21 software, and the model was developed using the DTClab QSAR tool. Docking was performed using PyRx v0.8 software. ORCA v5.0.1 computational package was used to optimize the structures. The job type used in optimization was equilibrium structure search using the DFT hybrid functional ORCA method B3LYP. The basis set was 6-311G (3df, 3pd) plus four polarization functions for all atoms. Accurate docking was performed for optimized leads using the iGEMDOCK v2.1 tool with a genetic algorithm by 10 solutions each of 80 generations. Molecular dynamic simulations were performed using GROMACS 2020.04 software with CHARMM36 all-atom force field.

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Data availability

Upon reasonable request, the corresponding author will provide the information supporting the study’s findings.

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Acknowledgements

The authors express their gratitude to Dr. V. B. Hrishikesan, Secretary, Sri Sankara Arts and Science College, Enathur, Kanchipuram, for providing valuable thoughts regarding the herbal plants and to the Principal Dr. K. R. Venkatesan, and the Management of Sri Sankara Arts and Science College, Enathur, Kanchipuram, for providing research facilities to carry out this work.

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Authors and Affiliations

  1. PG & Research Department of Biotechnology, Sri Sankara Arts and Science College, University of Madras, Enathur, Kanchipuram, Tamil Nadu, -631561, India

    Manoharan Harini, Vadivel Prabakaran, Anandan Krithika, Shanmugam Dinesh, Arumugam Rajalakshmi, Rengarajulu Puvanakrishnan & Balasubramanian Ramesh

  2. PG & Research Department of Microbiology, Sri Sankara Arts and Science College, University of Madras, Enathur, Kanchipuram, Tamil Nadu, -631561, India

    Kuppuswamy Kavitha & Gopal Suresh

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  1. Manoharan Harini
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Contributions

Manoharan Harini contributed to the literature search, performing experiments, and drafting the original version of the manuscript. Kuppuswamy Kavitha and Arumugam Rajalakshmi contributed to reviewing of manuscript and performing in silico molecular dynamic work. Vadivel Prabakaran contributed to sample collection and performing experimental work. Anandan Krithika and Shanmugam Dinesh contributed to performing in vitro experimental work and data collection. Gopal Suresh and Rengarajulu Puvanakrishnan contributed to the statistical analysis of the work and critical evaluation of the manuscript. Balasubramanian Ramesh was involved in the planning, supervision, and validation of the work and verification of the manuscript. All the authors reviewed the final version of the manuscript.

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Correspondence to Balasubramanian Ramesh.

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Harini, M., Kavitha, K., Prabakaran, V. et al. Identification of apigenin-4’-glucoside as bacterial DNA gyrase inhibitor by QSAR modeling, molecular docking, DFT, molecular dynamics, and in vitro confirmation studies. J Mol Model 30, 22 (2024). https://doi.org/10.1007/s00894-023-05813-z

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