Alzheimer's disease is a neurodegenerative disorder that causes significant cognitive impairment and memory loss. It is the leading cause of dementia on a global scale and is distinguished by the path Show more
Alzheimer's disease is a neurodegenerative disorder that causes significant cognitive impairment and memory loss. It is the leading cause of dementia on a global scale and is distinguished by the pathological build-up of amyloid-beta peptides and tau protein. This study presents the development of E-pharmacophore modeling, which utilizes reported co-crystal structure involving beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) to screen the eMolecules database. The present study comprehensively dealt with the virtual screening and structure-based prediction of thiazole compounds against BACE1 protein. To investigate the binding mode of virtual-screened hits (VS-hits), top 100 VS-hits were docked into BACE1 followed by in silico ADMET prediction. Top two VS-hits (CP1 and CP2) with highest docking scores along with co-crystalized ligand (CPZ) were further subjected to MESP, HOMO, LUMO, MD simulation, and MMGBSA analysis to inspect the dynamic stability of inhibitor-BACE1 complexes and the key molecular interaction responsible for their improved binding affinity toward BACE1. This research identified CP1 and CP2 as top two potential novel BACE1 inhibitors from the library of natural products, whose Glide docking scores range from -8.87 to -7.89 kcal/mol-1. Interestingly, both ligands were able to establish interactions with a set of conserved residues F108, I110, I118, L30, Q12, G13, G11, A335, S229, D228, G230, D32, G34, S35, and Y71. ADMET assessment of the selected compounds was also noted to be within acceptable ranges. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The RMSD and RMSF analysis revealed that both ligands remained stable and maintained their interaction throughout the simulation time (100 nanoseconds). The MM/GBSA (ranging from -36.734 to -27.431 kcal/mol) predicted binding affinities are in strong correlation with that of the docking score, which not only supports the docking results but also suggests that CP1 exhibits superior binding affinity towards BACE1. Keeping in view these findings, CP1 might be a promising candidate for drug discovery against BACE1 inhibitors. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious BACE1 inhibitors. Show less
Developing highly potent covalent inhibitors of Fibroblast growth factor receptors 1 (FGFR1) has always been a challenging task. In the current study, various computational techniques, such as 3D-QSAR Show more
Developing highly potent covalent inhibitors of Fibroblast growth factor receptors 1 (FGFR1) has always been a challenging task. In the current study, various computational techniques, such as 3D-QSAR, covalent docking, fingerprinting analysis, MD simulation followed by MMGB/PBSA, and per-residue energy decomposition analysis were used to explore the binding mechanism of pyrazolo[3,4-d]pyridazinone derivatives to FGFR1. The high q2 and r2 values for the CoMFA and CoMSIA models, suggest that the constructed 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The structural requirements revealed by the model's contour maps were strategically used to computationally create an in-house library of more than 100 new FGFR1 inhibitors using the R-group exploration technique implemented in the Spark Show less