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Comparative structural study of selective and non-selective NSAIDs against the enzyme cyclooxygenase-2 through real-time molecular dynamics linked to post-dynamics MM-GBSA and e-pharmacophores mapping

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Abstract

Background

Inflammation-provoked disorders including cancer are arbitrated by cyclooxygenase-2 (COX-2). Celecoxib and niflumic acid are among the potent and selective inhibitors of this enzyme while aspirin (acetylsalicylic acid) and sodium salicylate are its non-selective and lesser potent inhibitors. Despite these proven studies, the comparative structural study of these selective and non-selective molecules at atomistic scale in complex state with COX-2 that may answer this differential inhibitory behavior has not been accomplished spotlighting the imperative need of additional research in this area. Thus, this study was framed to provide a strong explanation for the enigma of higher inhibitory activity of celecoxib-niflumic acid duo in comparison to aspirin and sodium salicylate towards COX-2.

Methods

A contemporary approach including advanced molecular docking against COX2, molecular dynamics of receptor-ligand complexes, simulation-trajectory-backed MMGBSA for different time points, radius of gyration (Rg) calculations, and e-pharmacophores approach was employed to attain a rational conclusion.

Results

Our findings demonstrated the higher binding affinity of celecoxib and niflumic acid over aspirin and sodium salicylate against COX-2. Although both selective and non-selective COX-2 inhibitors manifested nearly the same stability in the active site of this enzyme but the e-pharmocophoric features found in the case of selective inhibitors scored over non-selective ones. Thus, our findings excluded the differential stability to be the cause of stronger potency of selective inhibitors but attributed their potency to greater number of complementary features present in these inhibitors against the active site of inflammation engendering COX-2.

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Data availability

All the data has been submitted as figures and tables with the manuscript.

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Acknowledgements

Rajamanikandan thanks Centre for Drug Discovery, Karpagam Academy of Higher Education, and Coimbatore for Molecular Dynamics. Malik FA sincerely thanks Rangaswamy R for providing the trial version of Schrödinger tool.

Author information

Authors and Affiliations

  1. Research Centre for Residue and Quality Analysis, FoH, SKUAST-Kashmir, Shalimar, Srinagar, 190025, Jammu & Kashmir, India

    Shabir Ahmad Ganai

  2. Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, 641021, Tamil Nadu, India

    Sundararaj Rajamanikandan

  3. Centre for Drug Discovery, Karpagam Academy of Higher Education, Coimbatore, 641021, Tamil Nadu, India

    Sundararaj Rajamanikandan

  4. Department of Biotechnology, University of Kashmir, Srinagar, 190006, Jammu & Kashmir, India

    Basit Amin Shah

  5. Department of Biochemistry, Deshbandhu College, University of Delhi, 110019, New Delhi, India

    Asif Lone

  6. Department of Veterinary Physiology, SKUAST-J-180009, Jammu, Jammu & Kashmir, India

    Faieza Arwa

  7. College of Temperate Sericulture, SKUAST-Kashmir, Mirgund, 193121, Jammu & Kashmir, India

    Firdose Ahmad Malik

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  1. Shabir Ahmad Ganai
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  4. Asif Lone
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Contributions

Ganai SA designed the work. Ganai SA and Rajamanikandan did majority of the work. Shah BA, Lone A, Arwa F, and Malik FA also contributed significantly. Ganai SA and Rajamanikandan wrote the manuscript.

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Correspondence to Shabir Ahmad Ganai.

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Ganai, S.A., Rajamanikandan, S., Shah, B.A. et al. Comparative structural study of selective and non-selective NSAIDs against the enzyme cyclooxygenase-2 through real-time molecular dynamics linked to post-dynamics MM-GBSA and e-pharmacophores mapping. J Mol Model 29, 192 (2023). https://doi.org/10.1007/s00894-023-05603-7

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