Studies on New Imidazo[2,1-b][1,3,4]thiadiazole Derivatives: Molecular Structure, Quantum Chemical Computational, and In silico Study of Inhibitory Activity Against Pim-1 Protein by using Molecular Modelling Methods and ADMET Profiling
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Imidazothiadiazole derivatives (KITD4 and KITD10) have been synthesized and characterized by NMR (1H&13C) spectra and single-crystal X-ray diffraction techniques. Density functional theory (DFT) calculations were performed to investigate the effect of substituents on the structures and intramolecular charge transfer (ICT) using natural bond orbital (NBO) analysis. Furthermore, DFT studies were extended to investigate the reactive sites of the title compounds through the molecular electrostatic potential (MEP) and frontier molecular orbitals (FMOs), including HOMO-LUMO, energy gap, and other chemical reactivity parameters. Hirshfeld surface and energy frameworks evaluated the different intermolecular interactions and energies based on the anisotropy of the topology. SwissADME drug design server predicted the oral bioavailability in the physicochemical space and showed good pharmacokinetic properties based on the boiled egg model. In addition, in silico molecular docking studies were executed to predict the biological activity of the molecules, as anticancer, against Pim-1 protein (homo sapiens PDB id: 3A99) and revealed prominent interactions with the active site of both the ligands showing reasonable conformity with the reported cocrystal ligand interactions. Besides, molecular dynamics simulations of holoprotein confirmed the structural constancy and stability of the protein-ligand complexes with minimal deviation showing faithful convergence throughout the entire trajectory of simulations. Both the simulations justify the hydrogen bond formations of the compounds with the vital amino acid LYS67, which is very much crucial for the inhibition of Pim-1 protein and shows similar conformity of hydrophobic residues interactions.

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