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Structure-based pharmacophore modeling and DFT studies of Indian Ocean-derived red algal compounds as PI3Kα inhibitors

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Abstract

Phosphoinositide kinases (PIKs) are a type of lipid kinase that acts as an upstream activator of oncogenic signaling. Presently accessible therapeutic compounds have downsides, such as toxicity and dubious efficacy, as well as lengthy treatment durations, which have bred resistance. Here we attempt to screen the Indian Ocean-derived red algal compounds to be used as a promising lead for PI3Kα inhibitor development. Experimental structure of the PI3K alpha Isoform-Specific Inhibitor alpelisib complex-based pharmacophore model was constructed and used as key to mark off the suitable lead compounds from the pool of marine-derived red algal compounds of Indian Ocean. Besides, the study encompasses pharmacophore scaffold screening as well as physicochemical and pharmacokinetic parameter assessment. We employed molecular docking and molecular dynamics simulation to assess the binding type and stability of 21 red algal derivatives. Twelve compounds demonstrated a sustained binding mode within the PI3Kα binding pocket with an optimal protein backbone root-mean-square deviation, also prompted hydrogen bonding throughout the simulations, and also implies that these MNPs have firmly mediated the interaction with prime hinge region residues in the PI3Kα ATP binding pocket. DFT studies revealed that proposed compounds had the greatest occupied molecular orbital electrophilicity index, basicity, and dipole moment, all of which attributed their stability as well as binding affinity at the PI3Kα active site. Our study's findings revealed that CMNPD31054, CMNPD4798, CMNPD27861, CMNPD4799, CMNPD27860, CMNPD9533, CMNPD3732, CMNPD4221, CMNPD31058, CMNPD31052, CMNPD29281, and CMNPD31055 can be used as lead compounds for PI3KΑ isoform inhibitors design.

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Acknowledgements

The authors would like to thank the technical team of The Department of Bioinformatics, Sathyabama Institute of Science and Technology for their computational facilities

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  1. AV, JCH, RD and MD have contributed equally to this work.

Authors and Affiliations

  1. Department of Bioinformatics, Sathyabama Institute of Science and Technology, Chennai, India

    Archana vasuki & H. Jemmy christy

  2. Department of Biotechnology, Sathyabama Institute of Science and Technology, Chennai, India

    K. Renugadevi

  3. Department of Biotechnology, Siddaganga Institute of Technology, Tumkur, Karnataka, India

    Manjunath Dammalli

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JCH conceptualized the research topic and supervised its implementation; AV and RD designed the method, analyzed the data, and prepared figures/tables; JCH and MD wrote the manuscript; JCH and RD revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to H. Jemmy christy.

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vasuki, A., christy, H.J., Renugadevi, K. et al. Structure-based pharmacophore modeling and DFT studies of Indian Ocean-derived red algal compounds as PI3Kα inhibitors. Mol Divers (2023). https://doi.org/10.1007/s11030-023-10695-7

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