The sharp spurt in positive cases of novel coronavirus-19 (SARS-CoV-2) worldwide has created a big threat to human. In view to expedite new drug leads for COVID-19, Main Proteases (M pro) of novel Coronavirus (SARS-CoV-2) has emerged as a crucial target for this virus. Nitric oxide (NO) inhibits the replication cycle of SARS-CoV. Inhalation of nitric oxide is used in the treatment of severe acute respiratory syndrome. Herein, we evaluated the phenyl furoxan, a well-known exogenous NO donor to identify the possible potent inhibitors through in silico studies such as molecular docking as per target analysis for candidates bound to substrate binding pocket of SARS-COV-2 M pro. Molecular dynamics (MD) simulations of most stable docked complexes (M pro-22 and M pro-26) helped to confirm the notable conformational stability of these docked complexes under dynamic state. Furthermore, Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations revealed energetic contributions of key residues of M pro in binding with potent furoxan derivatives 22, 26. In the present study to validate the molecular docking, MD simulation and MM-PBSA results, crystal structure of M pro bound to experimentally known inhibitor X77 was used as control and the obtained results are presented herein. We envisaged that spiro-isoquinolino-piperidine-furoxan moieties can be used as effective ligand for SARS-CoV-2 M pro inhibition due to the presence of key isoquinolino-piperidine skeleton with additional NO effect.
Poor water solubility and slow dissolution rate are the prime issues for the majority of upcoming and existing biologically active compounds. Cefdinir is a poorly water-soluble drug and its bioavailability is very low from its crystalline form. The purpose of the present investigation was to increase the solubility and dissolution rate of Cefdinir by preparation of its nanosuspension by solvent evaporation technique. The prepared formulation of nanosuspension was evaluated for its particle size, total drug content, entrapment efficiency, saturation solubility and in vitro dissolution. The optimized formulation was spray dried to obtain nanoparticles. The prepared nanoparticles were then evaluated for their particle size, saturation solubility and in-vitro drug release and the results were compared with the pure drug. A 2 3 factorial design was employed to study the effect of independent variables, amount of PVPK-30 (X1), Poloxamer-188 (X2) and stirring rate (X3) on the dependent variables, particle size (nm,Y1) and in-vitro drug release (%, Y2). Validity of the developed mathematical equation was assayed by designing to check point. The results indicated the suitability of solvent evaporation method for Cefdinir with improved in vitro dissolution rate and thus perhaps enhance fast onset of action for the drug.
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