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Unravelling the molecular mechanistic pathway underlying the anticancer effects of kaempferol in colorectal cancer: a reverse pharmacology network approach

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Abstract

Colorectal cancer (CRC) is the third most diagnosed and highly fatal malignancy, presenting serious health concerns worldwide. The search for an effective cure for CRC is challenging and poses a serious concern. Kaempferol is a potent anti-cancerous bioactive compound often suggested for treating various cancers, including CRC. However, its underlying molecular mechanism against CRC remains unclear. The present study delves into kaempferol's molecular pathways and underlying molecular mechanisms against CRC targets. The target protein-coding genes for kaempferol were retrieved, and the CRC-associated genes were curated. Twelve common targets with a disease specificity index of > 0.6 were validated for their protein expression at different stages of CRC. Over-expressed USP1, SETD7, POLH, TDP1 and RACGAP1 were selected for further studies. The binding affinities of kaempferol to the corresponding proteins were evaluated using molecular docking and Molecular Dynamics (MD) simulations. SETD7 exhibited the highest binding affinity with the lowest binding energy (− 8.06 kcal/mol). Additionally, the MD simulation, and MM-PBSA conferred SETD7-kaempferol complex had the least root-mean-square deviation with lower interaction energy and higher conformational stability. The protein–protein interaction of SETD7 constructed revealed direct interactors, namely, DNMT1, FOXO1, FOXO3, FOXO4, H3-3B, H3-4, H3C12, H3C13, SETD7, SIRT1 and TP53, have a potential role in cancer progression through FOXO signalling. In summary, our study revealed kaempferol's multi-target and synergistic effect on multiple CRC targets and its underlying mechanisms. Finally, the study recommends in-vitro and in-vivo trials for validation of anti-cancerous drugs for CRC.

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The authors gratefully acknowledge the Indian Council of Medical Research (ICMR), New Delhi, Government of India agency, for the research grant (IRIS ID: 2021–11889).

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  1. Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Tamil Nadu, Vellore, 632014, India

    P. Priyamvada, Anand Anbarasu & Sudha Ramaiah

  2. Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Tamil Nadu, Vellore, 632014, India

    Tushar Joshi, Suvitha Anbarasu & Anand Anbarasu

  3. Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Tamil Nadu, Vellore, 632014, India

    P. Priyamvada, Gayathri Ashok & Sudha Ramaiah

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Conceptualization and methodology-P. P and G.A.; Validation and formal analysis- P.P, G.A and T.J; Investigation- A.A and S.R; writing-original draft preparation- P.P and G.A; Writing- review and editing- A.A and S.R; visualization- P.P., G.A. and S.A.; supervision- A.A and S.R.

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Priyamvada, P., Ashok, G., Joshi, T. et al. Unravelling the molecular mechanistic pathway underlying the anticancer effects of kaempferol in colorectal cancer: a reverse pharmacology network approach. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10890-0

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