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Novel B, C-ring truncated deguelin derivatives reveals as potential inhibitors of cyclin D1 and cyclin E using molecular docking and molecular dynamic simulation

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Abstract

The overexpression of cyclin D1 and cyclin E due to their oncogenic potential and amplification has been associated with a higher mortality rate in many cancers. The deguelin is a natural compound, has shown promising anti-cancer activity by directly binding cyclin D1 and cyclin E and thus suppressing its function. The C7a atomic position of deguelin structure contains a proton that generates stabilized radical, as a result, decomposed deguelin reduces its structural stability and significantly decreases its biological activity. To design deguelin derivatives with the reduced potential side effect, series of B, C-ring truncated derivatives were investigated as cyclin D1 and cyclin E inhibitors. R-group-based enumeration was implemented in the deguelin scaffold using the R-group enumeration module of Schrödinger. Drug-Like filters like, REOS and PAINs series were applied to the enumerated compound library to remove compounds containing reactive functional groups. Further, screened compounds were docked within the ligand-binding cavity of cyclin D1 and cyclin E crystal structure, using Glide SP and XP protocol to obtain docking poses. Enrichment calculations were done using SchrÖdinger software, with 1000 decoy compounds (from DUD.E database) and 60 compounds (XP best poses) along with deguelin, to validate the docking protocol. The receiver operating characteristic (ROC) curve indicates R2 = 0.94 for cyclin D1 and R2 = 0.79 for cyclin E, suggesting that the docking protocol is valid. Besides, we explored molecular dynamics simulation to probe the binding stability of deguelin and its derivatives within the binding cavity of cyclin D1 and cyclin E structures which are associated with the cyclin D1 and cyclin E inhibitory mechanism.

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The docking structures are available upon request from the corresponding author.

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Acknowledgements

The authors are thankful to DYPBBI (Dr. D. Y. Patil Biotechnology and Bioinformatics Institute) Dr. D. Y. Patil Vidyapeeth Tathawade, Pune, for providing the infrastructure and facilities to perform this study. The authors also acknowledge the DST-SERB, Govt. of India, New Delhi, (File Number: YSS/2015/002035) for Optimized Supercomputer facility for dynamics calculations. Mr. Kiran Bharat Lokhande acknowledges the ICMR (Indian Council of Medical Research), New Delhi, India, for Senior Research Fellowship (Project ID: 2019-3458; file: ISRM/11(54)/2019). The authors acknowledge the support of the Bioinformatics Centre, Savitribai Phule Pune University, Pune, for providing Schrodinger software for free energy calculations. The authors also would like to acknowledge the support of Schrodinger and the team for providing an Evaluation License to our Bioinformatics Research Laboratory.

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This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Bioinformatics Research Laboratory, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Pune, 411033, India

    Kiran Bharat Lokhande, Shuchi Nagar & K. Venkateswara Swamy

  2. Bioinformatics Centre, Savitribai Phule Pune University, Pune, 411007, India

    Payel Ghosh

  3. Bioinformatics and Drug Discovery Group, MIT School of Bioengineering Science & Research, MIT Art, Design and Technology University, Pune, 412201, India

    K. Venkateswara Swamy

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Lokhande, K.B., Ghosh, P., Nagar, S. et al. Novel B, C-ring truncated deguelin derivatives reveals as potential inhibitors of cyclin D1 and cyclin E using molecular docking and molecular dynamic simulation. Mol Divers 26, 2295–2309 (2022). https://doi.org/10.1007/s11030-021-10334-z

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