In silico hit optimization toward AKT inhibition: fragment-based approach, molecular docking and molecular dynamics study

Abstract

Protein kinase B also known as AKT is a cardinal node in different signaling pathways that regulates diverse cell processes. AKT has three isoforms that share high homology. Hyperactivation of each isoform is related with different types of cancer. This work describes the computational search for new inhibitors using a hit optimization process of the previously reported AKT pan inhibitor, a 2,4,6-trisubstituted pyridine. A database of new molecules was proposed using a variant of fragment-based docking methodology and previous reported considerations. Molecular docking followed by molecular dynamics studies were performed to select the best compounds and analyze their behavior. Protein–ligand complexes energy was calculated using molecular mechanics Poisson–Boltzmann surface area protocol. Further, proposed molecules were compared with the ChEMBL database of compounds assayed against AKT. Data analysis leads to determine the structural requirements necessary for a favorable interaction of the proposed ligands with the AKT pocket. Molecular dynamics data suggested that the pK_a of the ligands is important for the stability in the AKT pocket. Molecular similarity analysis shows that proposed ligands have not been previously reported. Thus, ligands with high docking scores and favorable behavior on molecular dynamics simulations are proposed as potential AKT inhibitors.

Keywords:

• AKT inhibitors
• cancer
• fragment-based docking
• 2,4,6-trisubstituted pyridine
• serine–threonine kinase B

Acknowledgements

The authors acknowledge DGESCA for the use of the supercomputer Miztli in project LANCAD-UNAM-DGTIC-285. The authors thank Dr. Antonio Romo-Mancillas for his valuable contributions to this work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors thank CONACyT for the financial support granted to the project [CB-251807]. EESC and IBC are grateful to CONACyT for the fellowships granted [Nos. 273595 and 521238], respectively.