An in silico approach to identify novel and potential Akt1 (protein kinase B-alpha) inhibitors as anticancer drugs
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Date
2025
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Nature
Abstract
Akt1 (protein kinase B) has become a major focus of attention due to its significant functionality in a variety of cellular processes and the inhibition of Akt1 could lead to a decrease in tumour growth effectively in cancer cells. In the present work, we discovered a set of novel Akt1 inhibitors by using multiple computational techniques, i.e. pharmacophore-based virtual screening, molecular docking, binding free energy calculations, and ADME properties. A five-point pharmacophore hypothesis was implemented and validated with AADRR38. The obtained R2 and Q2 values are in the acceptable region with the values of 0.90 and 0.64, respectively. The generated pharmacophore model was employed for virtual screening to find out the potential Akt1 inhibitors. Further, the selected hits were subjected to molecular docking, binding free energy analysis, and refined using ADME properties. Also, we designed a series of 6-methoxybenzo[b]oxazole analogues by comprising the structural characteristics of the hits acquired from the database. Molecules D1–D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein–ligand complex. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.
Description
Keywords
6 methoxybenzo[b]oxazole, 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one, afuresertib, albumin, antineoplastic agent, bay1125976, capivasertib, ipatasertib, miransertib, n (3 (6 methoxybenzo[d]oxazol 2 yl) pyridin 2 yl)acetamide analogue, protein kinase B inhibitor, unclassified drug, uprosertib, AKT1 protein, human, ligand, protein binding, protein kinase B, protein kinase inhibitor, Article, binding affinity, binding energy, binding free energy analysis, blood brain barrier, cancer therapy, chemical structure, clinical trial (topic), computer model, conformational transition, correlation coefficient, crystal structure, hydrogen bond, hydrophobicity, IC50, intestine absorption, Ligand interaction diagram, measurement precision, metabolic clearance, molecular docking, molecular dynamics, partition coefficient, permeability, pharmacokinetic parameters, pharmacophore, quantitative structure activity relation, radius of gyration, root mean squared error, Scatter plot, Solvent Accessible Surface Area, surface area, three-dimensional imaging, training, tumor growth, virtual screening, water solubility, X ray analysis, chemistry, computer simulation, drug design, drug development, human, metabolism, procedures, thermodynamics, Antineoplastic Agents, Computer Simulation, Drug Design, Drug Discovery, Humans, Ligands, Molecular Docking Simulation, Molecular Dynamics Simulation, Protein Binding, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Thermodynamics
Citation
Molecular Diversity, 2025, 29, 2, pp. 1009-1032