In-silico investigation of 4-nitro-N-1H-pyrazol-3-ylbenzamide towards its potential use against SARS-CoV-2: a DFT, molecular docking and molecular dynamics study.

In the present research work, we report the synthesis and characterization of novel pyrazole derivative obtained by the condensation reaction of 4-nitro benzaldehyde group with one equivalent of the 2-amino pyrazole yielding 4-nitro-N-1H-pyrazol-3-ylbenzamide with high yield. The two symmetry-independent molecules (molecule A and molecule B) differ about the central C-N bond, with the dihedral angles between the pyrazole ring system and the nitrobenzene ring being 13.90° and 18.64°, respectively. By optimizing the symmetry-independent dimer molecules, the rotational barrier between the conformers is found to be within the 2.5-5.5 kcal/mol range. QTAIM and RDG based NCI isosurface revealed the presence of strong N-H…N and C-H…O hydrogen bonds which stabilize the two independent centrosymmetric inversion-related dimers. Further, weak and short directional interactions such as C-H…N, H…H and C-H…π were also analyzed systematically using various topological parameters. The compound is found to adhere to the Lipinski's rule of five and exhibit good pharmacokinetic properties. The results of molecular docking studies performed against SARS-CoV-2 virus main protease (PDB IDs: 6LU7, 6W9C and 6WQF) revealed that the compound showed better docking scores. Molecular docking studies verified the inhibition activity of the synthesized novel compound. Finally, the binding free energy and contributed energies were calculated using MM-GBSA method. The 6LU7-ligand complex showed highest binding free energy and among all other interactions, the contributions of the covalent binding and van der Waals energy are found to be significant.Communicated by Ramaswamy H. Sarma.

Structural, computational and in silico studies of 4-bromo-3-flurobenzonitrile as anti-Alzheimer and anti-Parkinson agents.

A novel dimer of the 4-bromo-3-fluorobenzonitrile was crystallized and studied using a spectroscopic method such as the scanning electron microscope method. The computational simulations substantiated the structural analysis findings. The Hirshfeld surface analysis has been performed for visualizing, exploring and quantifying the intra and inter-molecular interactions that stabilize the crystal packing of the compound. The NBO and QTAIM analyses were applied to study the nature and origin of the attractive forces involved in the crystal structure. Further, the pharmacokinetic properties of the compound were evaluated, indicating good brain-blood barrier and central nervous system penetration capability. Hence, in silico studies was carried out to explore the binding pattern of the titled compound against acetylcholinesterase and butyrylcholinesterase, and tumor necrosis factor-alpha converting enzyme proteins using molecular docking and molecular dynamics simulations approach. Further, the titled compound is compared with standard drugs through molecular docking studies. The in silico studies finally predicts that the compound under investigation may act as a good inhibitor for treating Alzheimer's disease and further in vitro and in vivo studies may provide its therapeutic potential.Communicated by Ramaswamy H. Sarma.