Insilico molecular modelling to identify PDK-1 targeting agents based on its protein–protein docking interaction

Abstract

PDK1, an attractive cancer target that downstreams 23 other kinases towards cell growth, survival and metabolism has gaining attention due to allosteric effect of ligands bound to it. Generally, the drug design strategy using pharmacophores is either a single protein structure or ensemble or ligand-based. Apart from these methods, yet another new approach of protein–protein docking with state of art computational tool like Schrodinger Suite to generate pharmacophores based on the interacting partners of the protein is proposed in this work. The structure-based pharmacophoric features were picked up from docking the ten interacting partners of PDK1 and screened against the Enamine libraries containing protein–protein interacting compound collection, advanced, protein mimetic and allosteric compounds. High throughput virtual screening against the PIF pocket of PDK1 yields an indole scaffold. The identified indole derivative is proposed to be a strong activator that binds in the protein–protein interaction site of PDK1 which was further confirmed by molecular metadynamics simulations, free energy surface analysis and MM-GBSA calculations. Thus, the pharmacophores generated by the interacting proteins for PPI can facilitate the virtual screening in structure-based drug discovery of similar therapeutic targets.

Communicated by Ramaswamy H. Sarma

Keywords:

• Protein–protein interaction
• phosphoinositide dependent kinase-1
• PIF pocket
• pharmacophore
• virtual screening
• metadynamics simulations
• free energy surface
• allostery

Acknowledgement

The authors thank the Council for Scientific and Industrial Research (CSIR), Govt. of India, NewDelhi for providing Senior Research Fellowship through the Scientists’ pool scheme.

Authors’ contributions

Both authors equally contributed to the work and approved the final version of the manuscript.

Disclosure statement

The authors declare that there is no conflict of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.