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<p>Pathogenic fungi, particularly <i>Candida albicans</i>, have been&#xa0;escalating clinical problems, notably because of antifungal resistance and symptomatological comorbidity with COVID-19. This research aimed to find phytochemical inhibitors of ergosterol production, specifically targeting ERG6 (C-24 sterol methyltransferase), utilizing chemicals from the IMPPAT database. A total of 14,965 phytochemicals were computationally evaluated against AlphaFold-predicted ERG6 utilizing AutoDock Vina. Fifteen compounds exhibiting robust binding affinities (− 8.2 to − 9.2&#xa0;kcal/mol) were found, from which four candidates were chosen based on advantageous ADMET profiles. The docking scores for the top four compounds targeting ERG6—Daturataturin A (− 8.8&#xa0;kcal/mol), Disogluside (− 8.6), Tataramide B (− 8.4), and Floribundasaponin A (− 8.4)—exceeded those of previously identified ERG6 inhibitors D28 (− 8.0), Tomatidine (− 7.9), and H55 (− 6.4). The selected leads were further docked against other proteins associated with drug resistance and cell proliferation, specifically ERG1, ERG11, CLB2, CDR1, and CDR2. Among these, only ERG1 exhibited significant interactions, with Disogluside (− 9.3&#xa0;kcal/mol), Tataramide B (− 9.9), and Floribundasaponin A (− 9.3) surpassing the reference inhibitor terbinafine (− 8.7&#xa0;kcal/mol), except for Daturataturin A, which showed a comparable score of − 8.6&#xa0;kcal/mol. Nevertheless, owing to steric conflicts inside the ERG1 binding sites, molecular dynamics (MD) simulations were conducted exclusively for ERG6-ligand complexes over duration of 100&#xa0;ns. The RMSD values demonstrated commendable structural stability: Daturataturin A (~ 0.39&#xa0;nm), Disogluside (~ 0.38&#xa0;nm), Tataramide B (~ 0.27&#xa0;nm), and Floribundasaponin A (~ 0.40&#xa0;nm). Principal Component Analysis (PCA) validated consistent and significant movements for Daturataturin A and Floribundasaponin A, whereas Disogluside and Tataramide B exhibited increased flexibility. MM/PBSA analysis indicated robust binding free energies for Daturataturin A (− 42.26&#xa0;kcal/mol), Floribundasaponin A (− 37.48&#xa0;kcal/mol), and Disogluside (− 29.58&#xa0;kcal/mol), however Tataramide B exhibited a detrimental + 9.81&#xa0;kcal/mol. These results endorse the promise of phytochemical-derived antifungals and necessitate more experimental verification.</p> Graphical abstract <p></p>

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In silico screening of IMPPAT-derived phytochemicals targeting ERG6 and drug resistance–associated proteins in drug-resistant Candida albicans: virtual screening and molecular dynamics using alphafold models

  • 期刊论文

  • 发表日期：

    2026年1月14日

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  • Akshay Kisan Mundhe,
  • Premanand Adaikalasamy,
  • Reena Rajkumari Baskaran

摘要

Pathogenic fungi, particularly Candida albicans, have been escalating clinical problems, notably because of antifungal resistance and symptomatological comorbidity with COVID-19. This research aimed to find phytochemical inhibitors of ergosterol production, specifically targeting ERG6 (C-24 sterol methyltransferase), utilizing chemicals from the IMPPAT database. A total of 14,965 phytochemicals were computationally evaluated against AlphaFold-predicted ERG6 utilizing AutoDock Vina. Fifteen compounds exhibiting robust binding affinities (− 8.2 to − 9.2 kcal/mol) were found, from which four candidates were chosen based on advantageous ADMET profiles. The docking scores for the top four compounds targeting ERG6—Daturataturin A (− 8.8 kcal/mol), Disogluside (− 8.6), Tataramide B (− 8.4), and Floribundasaponin A (− 8.4)—exceeded those of previously identified ERG6 inhibitors D28 (− 8.0), Tomatidine (− 7.9), and H55 (− 6.4). The selected leads were further docked against other proteins associated with drug resistance and cell proliferation, specifically ERG1, ERG11, CLB2, CDR1, and CDR2. Among these, only ERG1 exhibited significant interactions, with Disogluside (− 9.3 kcal/mol), Tataramide B (− 9.9), and Floribundasaponin A (− 9.3) surpassing the reference inhibitor terbinafine (− 8.7 kcal/mol), except for Daturataturin A, which showed a comparable score of − 8.6 kcal/mol. Nevertheless, owing to steric conflicts inside the ERG1 binding sites, molecular dynamics (MD) simulations were conducted exclusively for ERG6-ligand complexes over duration of 100 ns. The RMSD values demonstrated commendable structural stability: Daturataturin A (~ 0.39 nm), Disogluside (~ 0.38 nm), Tataramide B (~ 0.27 nm), and Floribundasaponin A (~ 0.40 nm). Principal Component Analysis (PCA) validated consistent and significant movements for Daturataturin A and Floribundasaponin A, whereas Disogluside and Tataramide B exhibited increased flexibility. MM/PBSA analysis indicated robust binding free energies for Daturataturin A (− 42.26 kcal/mol), Floribundasaponin A (− 37.48 kcal/mol), and Disogluside (− 29.58 kcal/mol), however Tataramide B exhibited a detrimental + 9.81 kcal/mol. These results endorse the promise of phytochemical-derived antifungals and necessitate more experimental verification.

Graphical abstract