Etikyala, U.Reddyrajula, R.Vani, T.Kuchana, V.Udayakumar, U.Vijjulatha, V.2026-02-032025Molecular Diversity, 2025, 29, 2, pp. 1009-103213811991https://doi.org/10.1007/s11030-024-10887-9https://idr.nitk.ac.in/handle/123456789/20344Akt1 (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 2024.6 methoxybenzo[b]oxazole8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) oneafuresertibalbuminantineoplastic agentbay1125976capivasertibipatasertibmiransertibn (3 (6 methoxybenzo[d]oxazol 2 yl) pyridin 2 yl)acetamide analogueprotein kinase B inhibitorunclassified druguprosertibAKT1 protein, humanligandprotein bindingprotein kinase Bprotein kinase inhibitorArticlebinding affinitybinding energybinding free energy analysisblood brain barriercancer therapychemical structureclinical trial (topic)computer modelconformational transitioncorrelation coefficientcrystal structurehydrogen bondhydrophobicityIC50intestine absorptionLigand interaction diagrammeasurement precisionmetabolic clearancemolecular dockingmolecular dynamicspartition coefficientpermeabilitypharmacokinetic parameterspharmacophorequantitative structure activity relationradius of gyrationroot mean squared errorScatter plotSolvent Accessible Surface Areasurface areathree-dimensional imagingtrainingtumor growthvirtual screeningwater solubilityX ray analysischemistrycomputer simulationdrug designdrug developmenthumanmetabolismproceduresthermodynamicsAntineoplastic AgentsComputer SimulationDrug DesignDrug DiscoveryHumansLigandsMolecular Docking SimulationMolecular Dynamics SimulationProtein BindingProtein Kinase InhibitorsProto-Oncogene Proteins c-aktThermodynamics