Khatabi, Khalil ElEl-Mernissi, RedaHajji, HalimaSingh, Atul KumarAjana, Mohammed AzizLakhlifi, TaharKumar, ShashankBouachrine, Mohammed2024-01-162024-08-132024-01-162024-08-132022-04-092069583710.33263/BRIAC131.076https://doi.org/10.33263/BRIAC131.076http://10.2.3.109/handle/32116/2874The ?-amylase is regarded as a promising drug target for diabetes mellitus-type II. Hence, inhibiting ?-amylase activity is a potential drug discovery approach for treating this chronic metabolic disorder. The present study explores the structural requirements and understands the inhibition mechanism of the novel developed indole-based derivatives as ?-amylase inhibitors through 3D-QSAR, molecular docking, ADMET, and molecular dynamics (MD) simulation. The 3D-QSAR study showed good statistical reliability for two developed predictive models; CoMFA and CoMSIA. Through a deep investigation of docking analysis, detailed interactions with ?-amylase of the most active compound 7 were explored. Four new indole derivatives were designed based on the contour maps and docking analysis, with significantly higher inhibitory activity than the molecules in the dataset. The selected molecules were evaluated for pharmacokinetic properties, showing a reasonably good ADMET profile. Furthermore, a 20-ns MD simulation of selected compounds bound to ?-amylase was performed to ensure stability during simulation further. Greater stability of the designed molecule-protein complex A1 was found. The present findings shed light on the binding mode and the interactions between newly designed compounds, especially compound A1 and ?-amylase and may be beneficial for drug development efforts targeting type-II diabetes. � 2022 by the authors.en-USIn silico ADMETIndoleMolecular dockingMolecular dynamics simulationType 2 diabetes?-amylaseArticle