Targeting Als3 adhesin of clinically relevant Candida species using natural carotenoids: an in-silico study

Candidemia, caused by the opportunistic Candida spp., poses a severe global health threat, characterized by mortality rates reaching 75% and the increasing prevalence of multidrug-resistant biofilms. In this study, we targeted the Agglutinin-Like Sequence 3 (Als3) adhesin protein, the primary mediator of Candida species attachment, as a non-lethal strategy to inhibit biofilm formation. Using molecular docking, we screened a library of 1570 natural carotenoids against the conserved N-terminal domain of Als3 of Candida albicans and compared to five positive controls. Our virtual screening identified five compounds (mangicrocin, MODU, α-zeacarotene-3,17'-diol, BTTB, and (15Z)-zeaxanthin-3'-rhamnoside), with the best binding pose and the least binding energy. Among them, mangicrocin showed best binding affinity (docking score - 7.18 kcal/mol, ΔG_bind - 35.23 kcal/mol) against C. albicans Als3, compared to the in vitro and in silico positive control, rutin (docking score - 5.772 kcal/mol, ΔG_bind - 30.59). It consistently achieved the best docking scores across C. albicans Als family proteins (Als1 and Als5) and Als3 proteins of other species in the Candida genus like C. auris, C. tropicalis, C. parapsilosis, and C. dubliniensis. Molecular electrostatic potential (MESP) mapping analysis further clarified that the hydrophobic polyene backbone and the negative electrostatic potential of the OH groups on the aromatic rings aid in anchorage to the key cadherin-binding residues-Lys59 and Ser170 in the Als3 binding pocket. Density Functional Theory (DFT) analysis shows high electrophilicity and a narrow energy gap contributes to mangicrocin's interactions and chemical reactivity. Molecular dynamics simulations suggested stable retention of mangicrocin within the Als3 binding pocket, supported by stable structural parameters and favorable interaction energy profiles. In silico ADMET profiling concludes these top five hits had limited toxicity and are druggable. As this study is entirely computational, these findings are predictive and require future in vitro validation to confirm biological efficacy.