Taylor & Francis Group
Browse
tbsd_a_1675536_sm3167.pdf (870.93 kB)

Computationally guided identification of Akt-3, a serine/threonine kinase inhibitors: Insights from homology modelling, structure-based screening, molecular dynamics and quantum mechanical calculations

Download (870.93 kB)
Version 2 2019-10-14, 10:41
Version 1 2019-10-08, 07:45
journal contribution
posted on 2019-10-14, 10:41 authored by Shubham Srivastava, Pakhuri Mehta, Omprakash Sharma, Manish Sharma, Ruchi Malik

Chemical entities targeting kinase signalling pathways serve as a potential strategy to combat malignancies. Protein Kinase B or Akt is a validated target for various malignancies and Akt3 remains the least explored isoform among all its isoforms. Initially, homology modelling technique was used for generating protein structure and further validation was performed using molecular dynamics simulation and Ramachandran plot. The validated protein structure was then subjected for active site analysis which led to identification of active site residues based on metrics provided by site score. The important residues in binding site were identified as Thr81, Asp271 and Asp289 for binding energetics and inhibition. Subsequently, virtual screening methodologies were used for identification of novel hits for inhibition of Protein Kinase B or Akt3. This led to the identification of two hits, i.e. thiophene derivative and thieno-pyridine derivative which were selected on the basis of their binding affinity and drug likeliness. These identified hits were subjected for molecular dynamics simulations, quantum mechanical and synthetic accessibility studies. The role of crucial residues in binding site stood validated as suggested by molecular dynamics simulations studies.

Communicated by Ramaswamy H. Sarma

Funding

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

History