Discovery of novel antifungal resorcylate aminopyrazole Hsp90 inhibitors based on structural optimization by molecular simulations.

Hsp90 is a highly conserved and essential stress protein located in all eukaryotes, involved in the regulation of fungal survival, virulence and resistance, which is an important target for the treatment of fungal infections. Here, we intended to discover a novel inhibitor against Hsp90 guided by theoretical 3-dimensional quantitative structure–activity relationship (3D-QSAR) models for aminopyrazole analogs, which were constructed by the comparative molecular field analysis (CoMFA) and the comparative molecular similarity index analysis (CoMSIA) models. The CoMFA (q² = 0.708, R² = 0.962) and CoMSIA (q² = 0.656, R² = 0.922) models had good stability and predictability, and their contour maps could provide 3D visual information for structural modification. Subsequently, all the inhibitors used in modeling were docked into the binding site of Hsp90 by the Surflex-Dock method and their interaction was explored, which indicated that inhibitor complexes to Hsp90 mainly relied on hydrogen bonds, Pi–S stacking and hydrophobic interactions. Then, we designed 10 novel candidates guided by contour maps and binding modes, and their potential anti-fungal activity and ADME/T profile were predicted by 3D-QSAR models and online tools, which showed the candidates with better potency and good ADME/T properties. We achieved the stable conformation of candidates (M7 and M9) complexed to Hsp90 by molecular dynamics (MD) simulations and evaluated their binding energy and energy contribution of amino acids by MM/PBSA. Compared to reports in the literature (compound 22: −44.725), the designed candidates (M7: −51.478, M9: −54.964) had better potency represented by binding energy. Based on the energy contribution of amino acids, we identified the key residues that interacted with candidates, such as Asp82, Thr174 and Leu37, which had a crucial role in increasing the binding affinity. Thus, our study could provide theoretical clues to design an inhibitor against Hsp90 which is used as an anti-fungal agent. [ABSTRACT FROM AUTHOR]