Integrated molecular docking, 3D QSAR and molecular dynamics simulation studies on indole derivatives for designing new Pim-1 inhibitors

Abstract

Pim-1 is one of the isoforms of pim proteins comprising pim-1, pim-2 and pim-3. It was basically recognized as proviral integration moloney murine leukemia virus which is associated with T-cell lymphomogenesis. Pim-1 is known to play a crucial role in cell cycle progression and acts as downstream target for the JAK/STAT signaling pathway. Recently it has emerged as a hopeful therapeutic target for cancer treatment as deregulation or over expression of pim causes hematologic cancers. In present article molecular docking based three dimensional quantitative structure and activity relationship and molecular dynamics simulation studies have been carried out on indole derivatives reported as pim-1 inhibitors. Initially docking was carried out to obtain the receptor specific orientation of the molecules and later to understand the structural requirements of pim-1 inhibitors robust 3 D QSAR models were built using CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) methods. The reliability of the models was established from conventional (r²) and cross validated (q²) values of 0.982, 0.524 for CoMFA and 0.974, 0.586 for CoMSIA respectively. Further the predictive ability of the model was evaluated using a test set of 17 molecules. The docking studies revealed that interaction with Glu 121 is vital for binding of inhibitors to pim-1. Based on the outcome of the results new molecules with improved activity were designed. Furthermore, MD simulations were also performed to examine the stability of interactions and investigate the pivotal role of Glu 121.

Keywords:

• Pim-1
• indole derivatives
• CoMFA
• CoMSIA
• molecular dynamics simulations

Acknowledgements

We greatly acknowledge Tripos Inc., USA and Schrödinger LLC, New York for providing the software. The author Peddi Sudhir Reddy would like to acknowledge financial support from UGC for a research fellowship.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Council of Scientific and Industrial Research [02(0379)/19/EMR-II] and Department of Science and Technology [DST PURSE-II/2017].