Tinospora cordifolia bioactive compounds as a novel sterol 14a-demethylase (CYP51) inhibitor: an in silico study.

In silico pharmacology Pub Date : 2025-02-13 eCollection Date: 2025-01-01 DOI:10.1007/s40203-025-00312-w

Kolawole T Mesileya, Precious C Onyeka, Iyidola M Adaramola, Quareebat O Igbalaye, Damilola S Bodun, Wisdom K Alao, Salim Y Jibril, Mustapha S Mohammed, Adedayo S Bowaje, Adebisi M Adeleye, Olaposi I Omotuyi

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Abstract

Trypanosoma cruzi, the causative agent of Chagas disease, poses a life-threatening risk in both endemic and non-endemic regions. The parasite's survival depends on the production of sterols via the 14-α-demethylase (CYP51) metabolic pathway. Current treatments for Chagas disease are often associated with undesirable side effects and drug resistance. This study aimed to identify potential inhibitors of CYP51 using bioactive compounds derived from Tinospora cordifolia. A library of 122 compounds from T. cordifolia was screened against CYP51 using the Glide docking model in the Maestro-Schrodinger suite (2022). The top four leads were evaluated through e-pharmacophore modeling, pharmacokinetics (ADMET) analysis and molecular mechanics generalized Born surface area (MM-GBSA) calculations. The top four compounds exhibited superior binding affinity to CYP51 compared to the standard drug, benznidazole, with docking scores ranging from - 11.397 kcal/mol to - 9.539 kcal/mol. ADMET predictions suggested low cytotoxicity for these compounds. Among the leads, epicatechin and n-trans-caffeoyl tyramine showed the greatest stability, reduced flexibility, and compact conformations, making them promising candidates for further investigation. This study identifies potential inhibitors from T. cordifolia with high binding affinity and structural compatibility with CYP51. While these results are encouraging, further in vivo and in vitro studies are necessary to validate their efficacy as anti-Chagas agents.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00312-w.

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