Comprehensive molecular docking and dynamic simulations for drug repurposing of clinical drugs against multiple cancer kinase targets

Abstract

Drug repurposing is a method to identify novel therapeutic agents from the existing drugs and clinical compounds. In the present comprehensive work, molecular docking, virtual screening and dynamics simulations were carried out for ten cancer types viz breast, colon, central nervous system, leukaemia, melanoma, ovarian, prostate, renal and lung (non-small and small cell) against validated eighteen kinase targets. The study aims to understand the action of chemotherapy drugs mechanism through binding interactions against selected targets via comparative docking simulations with the state-art molecular modelling suits such as MOE, Cresset–Flare, AutoDock Vina, GOLD and GLIDE. Chemotherapeutic drugs (n = 112) were shortlisted from standard drug databases with appropriate chemoinformatic filters. Based on docking studies it was revealed that leucovorin, nilotinib, ellence, thalomid and carfilzomib drugs possessed potential against other cancer targets. A library was built to enumerate novel molecules based on the scaffold and functional groups extracted from known drugs and clinical compounds. Twenty novel molecules were prioritised further based on drug-like attributes. These were cross docked against 1MQ4 Aurora-A Protein Kinase for prostate cancer and 4UYA Mitogen-activated protein kinase for renal cancer. All docking programs yielded similar results but interestingly AutoDock Vina yielded the lowest RMSD with the native ligand. To further validate the final docking results at atomistic level, molecular dynamics simulations were performed to ascertain the stability of the protein–ligand complex. The study enables repurposing of drugs and lead identification by employing a host of structure and ligand based virtual screening tools and techniques.

Communicated by Ramaswamy H. Sarma

Keywords:

• Drug repurposing
• chemotherapeutic drugs
• molecular docking
• virtual screening
• structure-based drug designing (SBDD)
• molecular simulation (MD)

Acknowledgments

The authors would like to thank the Director, MIT School of Bioengineering Sciences & Research for infrastructure support NS thanks to MIT Art, Design and Technology University, Rajbaugh Campus, Loni Kalbhor, Pune for awarding a Ph.D. research fellowship. All authors thank Schrodinger Inc, and Cresset Flare for providing an evaluation licence for the study.

Disclosure statement

The authors declare no conflict of interest.

Data availability statement

The docking and dynamics structures are available upon request from the corresponding author.

Additional information

Funding

Funding from MIT Art Design and Technology University Pune India is duly acknowledged for grant of PhD fellowship to NS.