Computational drug repurposing of Akt-1 allosteric inhibitors for non-small cell lung cancer

Krishnaprasad Baby, Swastika Maity, Chetan Hasmukh Mehta, Usha Y. Nayak, Gautham G. Shenoy, Karkala Sreedhara Ranganath Pai, Kuzhuvelil B. Harikumar, Yogendra Nayak

Research output: Contribution to journalArticlepeer-review


Non-small cell lung carcinomas (NSCLC) are the predominant form of lung malignancy and the reason for the highest number of cancer-related deaths. Widespread deregulation of Akt, a serine/threonine kinase, has been reported in NSCLC. Allosteric Akt inhibitors bind in the space separating the Pleckstrin homology (PH) and catalytic domains, typically with tryptophan residue (Trp-80). This could decrease the regulatory site phosphorylation by stabilizing the PH-in conformation. Hence, in this study, a computational investigation was undertaken to identify allosteric Akt-1 inhibitors from FDA-approved drugs. The molecules were docked at standard precision (SP) and extra-precision (XP), followed by Prime molecular mechanics-generalized Born surface area (MM-GBSA), and molecular dynamics (MD) simulations on selected hits. Post XP-docking, fourteen best hits were identified from a library of 2115 optimized FDA-approved compounds, demonstrating several beneficial interactions such as pi-pi stacking, pi-cation, direct, and water-bridged hydrogen bonds with the crucial residues (Trp-80 and Tyr-272) and several amino acid residues in the allosteric ligand-binding pocket of Akt-1. Subsequent MD simulations to verify the stability of chosen drugs to the Akt-1 allosteric site showed valganciclovir, dasatinib, indacaterol, and novobiocin to have high stability. Further, predictions for possible biological interactions were performed using computational tools such as ProTox-II, CLC-Pred, and PASSOnline. The shortlisted drugs open a new class of allosteric Akt-1 inhibitors for the therapy of NSCLC.

Original languageEnglish
Pages (from-to)7947
Number of pages1
JournalScientific Reports
Issue number1
Publication statusPublished - 16-05-2023

All Science Journal Classification (ASJC) codes

  • General


Dive into the research topics of 'Computational drug repurposing of Akt-1 allosteric inhibitors for non-small cell lung cancer'. Together they form a unique fingerprint.

Cite this