In-silico identification of 3,4-Diarylpyrazoles-based small molecules as potential Hsp90 inhibitors

• Small molecules-based inhibition of Hsp90 is an emerging cancer therapy. • In silico approaches are valuable in identifying bioactive small molecules. • Pyrazole-based molecules can serve as potent anticancer agents targeting Hsp90. The ATP-dependent molecular chaperone, Hsp90, is crucial for the activity of hundreds of client proteins. Several of Hsp90 clients are involved in cancer cell growth and proliferation. Thus, numerous Hsp90 inhibitors have been developed to target Hsp90′s ATPase activity in cancer cells. CCT018159 is a pyrazole-based compound that successfully inhibited Hsp90 oncogenic activity by binding deeply to the ATP binding pocket in the Hsp90 N-terminal domain (N-Hsp90). In the present study, we utilized the CCT018159 structure to identify new potential Hsp90 inhibitors using a set of in-silico approaches. The ZINC database was virtually screened for CCT018159 analogs using the SwissSimilarity webpage. Ten molecules were selected for further investigation based on their drug-likeness, pharmacokinetics, and physiochemical properties. The molecular docking simulation analysis revealed that these ZINC compounds have Ligand Binding Energies (LBEs) ranging from −8.61 to −9.73 Kcal/mol, which reflects a high binding affinity compared to CCT018159 (LBE of −6.31 Kcal/mol). These compounds exhibited diverse interactions, including critical hydrogen bonds and hydrophobic contacts with crucial residues like Asn51, Ala55, and Leu107. Further optimization targeting unique interactions (e.g., ZINC000008973382 with Asp93, Met98, and Thr184) and exploiting the versatile Lys58 could lead to novel, potent anticancer agents targeting Hsp90.