Identification of new small molecules as dual FoxM1 and Hsp70 inhibitors using computational methods

Zahra Alimardan; Maryam Abbasi; Ghadamali Khodarahmi; Khosrow Kashfi; Farshid Hasanzadeh; Aghaei Mahmud

doi:10.4103/1735-5362.359431

Identification of new small molecules as dual FoxM1 and Hsp70 inhibitors using computational methods

Res Pharm Sci. 2022 Oct 29;17(6):635-656. doi: 10.4103/1735-5362.359431. eCollection 2022 Dec.

Authors

Zahra Alimardan^{1

2}, Maryam Abbasi³, Ghadamali Khodarahmi^{1

2}, Khosrow Kashfi^{4

5

6}, Farshid Hasanzadeh¹, Aghaei Mahmud^{2

7}

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.
² Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.
³ Department of Medicinal Chemistry, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, I.R. Iran.
⁴ Department of Molecular, Cellular, and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA.
⁵ Graduate Program in Biology, City University of New York Graduate Center, New York, USA.
⁶ Department of Chemistry and Physics, State University of New York at Old Westbury, New York, USA.
⁷ Department of Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.

Abstract

Background and purpose: FoxM1 and Hsp70 proteins are highly expressed in many cancers. Thus, their inhibition serves as Bonafede targets in cancer treatment.

Experimental approach: FDI-6, an inhibitor of FoxM1, was selected as a template, and based on its structure, a new library from the ZINC database was obtained. Virtual screening was then performed using the created pharmacophore model. The second virtual screening phase was conducted with molecular docking to get the best inhibitor for both FoxM1 and Hsp70 active sites. In silico, ADMET properties were also calculated. Finally, molecular dynamics simulation was performed on the best ligand, ZINC1152745, for both Hsp70 and FoxM1 proteins during 100 ns.

Findings / results: The results of this study indicated that ZINC1152745 was stable in the active site of both proteins, Hsp70 and FoxM1. The final scaffold identified by the presented computational approach could offer a hit compound for designing promising anticancer agents targeting both FoxM1 and Hsp70.

Conclusion and implications: Molecular dynamics simulations were performed on ZINC1152745 targeting FoxM1 and Hsp70 active sites. The results of several hydrogen bonds, the radius of gyration, RMSF, RMSD, and free energy during the simulations showed good stability of ZINC1152745 with FoxM1 and Hsp70.

Keywords: Cancer; Dual inhibitor; FoxM1 and Hsp70 inhibitors; Molecular dynamics simulation; Pharmacophore modeling; Virtual screening.