Exploring CIP2A modulators using multiple molecular modeling approaches

Abstract

Like other human oncoproteins, Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) exerts cancer promoting function through interaction with other partner proteins, such as MYC and Protein Phosphatase 2A (PP2A). CIP2A regulates several MYC-independent and/or dependent gene expression programs. Broadly, CIP2A can inhibit PP2A, and especially it has been shown to inhibit MYC-associated PP2A, precisely to increase MYC stability and function. Availability of crystal structure has broached the research focus to develop new therapeutics targeting CIP2A. In the present study, structural information of the protein has been used for identification of modulators for homo-dimer CIP2A using advanced structure-based drug design approaches. The compound library, ‘Maybridge Screening Collection’ database (∼62,000 compounds) has been virtually screened to find out potent modulators for CIP2A. Identification of hotspot region on CIP2A protein-protein interaction interface has been performed using three different tools (HotPoint, SiteMap and icmPocketFinder). Thereafter, molecular docking (Extra Precision and Induced Fit Docking), and long range molecular dynamics simulation analysis, and ADME profile analysis have been carried out for screening purposes. Calculations of MM-PBSA based binding free energy (ΔG), and Density Functional Theory for quantum chemical simulations have been carried out for the hit compounds obtained through multi-step molecular docking based virtual screening technique. The multi-chemometric studies suggested that hit modulators have formed significant numbers of molecular interactions with hotspot residues in the homo-dimer interface region, which enable to hold CIP2A binding stability. Compounds with average ΔG values (ranging –3.4 x 10⁻² to −1.1 x 10⁻² KJ/mol) signifying promising CIP2A modulators.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cancer
• cancerous inhibitor of protein phosphatase 2A
• XP-docking
• induced fit docking
• molecular dynamics
• MM-PBSA
• DFT

Acknowledgements

Sincere thanks to Md. Ataul Islam for providing the computational resources (CHPC, Cape Town, South Africa).

Disclosure statement

The authors declare that they have no conflict of interest.

Additional information

Funding

The authors would like to thank TEQIP Phase-III and RUSA-II, University of Calcutta for providing financial support.