Discovery of small molecule inhibitors through pharmacophore modeling, molecular docking, molecular dynamics simulation and experimental validation against myeloid cell leukemia-1 (Mcl-1)

Abstract

Myeloid cell leukemia-1 (Mcl-1) protein is a family of Bcl-2 (B cell lymphoma 2) rich proteases of the most common increase threshold for genetic aberrations observed in human cancer, including lung, breast, pancreatic, cervical, and ovarian cancers as well as leukemia and lymphoma. Mcl-1 is recognized as an attractive drug target in number of diseases, including cancer. In the present study we surveyed and collected queries compounds from PDB database of Mcl-1 protein and generated pharmacophore-based models adapted to screen the drug-like compounds from FDA approved database. The 206 best lead molecules from pharmacophore-screening were further evaluated by molecular docking, molecular dynamics simulation, MM-GBSA calculation, as well as experimental validation. Two hits, ZINC00601272 and ZINC00002166, showed the best docking scores, which showed a tendency to inhibit cell viability of HL60 and K562 leukemia cells with Mcl-1 expressions. Conclusively, the present study provides structural information of Mcl-1 inhibitors for next generations of cancer therapeutics through computational and experimental validation approach.

Communicated by Ramaswamy H. Sarma

Keywords:

• Myeloid cell leukemia-1
• virtual screening
• MM/GBSA
• Molecular dynamics simulation

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The work was financially supported by the Overseas Expertise Introduction Project for Discipline Innovation (“111Project”) (Grant No. D20029), Program for Innovative Talents of Higher Education of Liaoning (2012520005), and virtual educational center of medicinal chemistry in Liaoning Province.