Molecular dynamics insights for PI3K-δ inhibition & structure guided identification of novel PI3K-δ inhibitors

Abstract

Conjugated structure based and ligand based drug design techinques have been used previously to unearth putative binding ligands for kinase inhibition. PI3K-δ is a lipid kinase and it has been found abberant in diseases such as cancer,inflammation etc. Preliminarily, protein crystal structure analysis suggest avaibility of two crystal structures with varying degree of root mean square de throughtion in protein back bone and root mean square fluctuation in side chain geometry. Therefore, PI3K-δ crystal structure was selected based on charactristic reciever operating characterstic curve and % enrichment of actives analysis. Active site analysis through molecular dynamics simulations provided insights about four residues Ile910, Asp911, Met752, Lys755, which act as flap. These residues fecilitate ligand binding in a unique manner.Thereafter, a validated designed protocol has been used to screen asinex ligand database using molecular docking and binding energy calculations. Based on binding affinity & energy scores and interaction pattern analysis total top 50 ligands were selected for PI3K-δ inhibition studies. Moreover, two molecules ethyl 2-(2-((4-chloro-1-methyl-1H-pyrazole-3-carbonyl) oxy)acetamido) benzo[1]thiazole-6-carboxylate and 1,6,7-trimethyl-8-((tetrahydrofuran-2-yl) methyl)-1H-imidazo [1',2':1,5] pyrrolo[3,2-d]pyrimidine-2,4(3H,8H)-dione have been identified, which could be potential hits for PI3K-δ using insights provided by molecular modelling studies. The identified compunds were subjected to pan assay interference compound filter and were found to be compliant. Quantum mechanical calculations were perfromed for identified hits. The above strategy could be implemented as a strategy for rational drug design.

Communicated by Ramaswamy H. Sarma

Keywords:

• virtual screening
• Pi3k-δ
• molecular dynamic simulations
• kinase
• flap dynamics

Acknowledgement

The authors would like to thank Central University of Rajasthan for providing basic infrastructure facilities. Shubham Srivastava would like to thank Council of Scientific and Industrial Research (CSIR) for providing Senior research fellowship with grant number 09/1131(0014)/18-EMR-I.

Disclosure statement

The authors declare no potential conflict of interest.

Additional information

Funding

Ruchi Malik would like to thank Department of Science and Technology- Rajasthan for research grant for pursuing present work acknowledgement number [P.7(3) S&T/R&D/2016/2616.] Shubham Srivastava would also like to thank DST- Rajasthan for providing junior research fellowship under the same grant.