Computational insights into binding mechanism of drugs as potential inhibitors against SARS-CoV-2 targets.

Because of the scale of the novel coronavirus (COVID-19) pandemic and the swift transmission of this highly contagious respiratory virus, repurposing existing drugs has become an urgent treatment approach. The objective of our study is to unravel the binding mechanism of the Food and Drug Administration (FDA)-approved dexamethasone (Dex) and boceprevir (Boc) drugs with selected COVID-19 protein targets SARS-CoV-2 spike protein C-terminal domain (spike-CTD), main protease (Mpro), and interleukin-6 (IL-6). Another objective is to analyze the effects of binding Dex and Boc drugs on the interactions of viral spike protein to human angiotensin-converting enzyme 2 (hACE2). Molecular docking and one-microsecond-long molecular dynamics simulations of each of the six protein-drug complexes along with steered molecular dynamics (SMD) and umbrella sampling (US) methods have revealed the binding mode interactions and the physicochemical stability of the three targeted proteins with two drugs. Results have shown that both drugs bind strongly with the three protein targets through hydrogen bonding and hydrophobic interactions. A major finding from this study is how the binding of the drugs with viral spike protein affects its interactions at the binding interface with hACE2 protein. Simulations of drug-bound spike-CTD with hACE2 show that due to the presence of a drug at the binding interface of spike-CTD, hACE2 is being blocked from making putative interactions with viral protein at such interface. These important findings regarding the binding affinity and stability of the two FDA-approved drugs with the main targets of COVID-19 along with the effect of drugs on hACE2 interactions would contribute to COVID-19 drug discovery and development. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-021-01843-0.

Lysozyme and Human Serum Albumin Proteins as Potential Nitric Oxide Cardiovascular Drug Carriers: Theoretical and Experimental Investigation.

Nitric oxide-containing drugs present a critical remedy for cardiovascular diseases. Nitroglycerin (NG, O-NO) and S-nitrosoglutathione (SNG, S-NO) are the most common nitric oxide drugs for cardiovascular diseases. Insights regarding the binding affinity of NO drugs with lysozyme and human serum albumin (HSA) proteins and their dissociation mechanism will provide inquisitive information regarding the potential of the proteins as drug carriers. For the first time, the binding interactions and affinities are investigated using molecular docking, conventional molecular dynamics, steered molecular dynamics, and umbrella sampling to explore the ability of both proteins to act as nitric oxide drug carriers. The molecular dynamics simulation results showed higher stability of lysozyme-drug complexes compared to HSA. For lysozyme, cardiovascular drugs were bound in the protein cavity mainly by the electrostatic and hydrogen bond interactions with residues ASP53, GLN58, ILE59, ARG62, TRP64, ASP102, and TRP109. For HSA, key binding residues were ARG410, TYR411, LYS414, ARG485, GLU450, ARG486, and SER489. The free energy profiles produced from umbrella sampling also suggest that lysozyme-drug complexes had better binding affinity than HSA-drug. Binding characteristics of nitric oxide-containing drugs NG and SNG to lysozyme and HSA proteins were studied using fluorescence and UV-vis absorption spectroscopy. The relative change in the fluorescence intensity as a function of drug concentrations was analyzed using Stern-Volmer calculations. This was also confirmed by the change in the UV-vis spectra. Fluorescence quenching results of both proteins with the drugs, based on the binding constant values, demonstrated significantly weak binding affinity to NG and strong binding affinity to SNG. Both computational and experimental studies provided important data for understanding protein-drug interactions and will aid in developing potential drug carrier systems in cardiovascular diseases.

Physicochemical stability study of protein-benzoic acid complexes using molecular dynamics simulations.

Carboxyl-modified substrates are the most common chemical moieties that are frequently used as protein defibrillators. We studied the stability of protein-benzoic acid complexes with bovine serum albumin (BSA), zein and lysozyme proteins using various computational methods. Structural model for zein was built using homology modelling technique and molecular docking was used to prepare complex structures of all three proteins with benzoic acid. Molecular dynamics calculations performed on these complex structures provided a strong support for the stability of protein-benzoic acid complexes. The results from various analyses including root-mean-square deviation (RMSD) and radius of gyration showed the stability and compactness of all proteins-benzoic acid complexes. Moreover, exploration of structural fluctuations in proteins revealed the stability of active site residues. Two potential binding modes of benzoic acid with all three proteins were identified via cluster analysis. The binding mode which was retrieved from top cluster containing 86-91% of total conformations displayed very strong binding interactions for zein, BSA and lysozyme proteins. In addition, the results of binding mode showed that various interactions, including hydrogen binding, hydrophobic and electrostatic interactions were important for the optimal binding of benzoic acid with the active sites of proteins. Exploration of solvent accessible surface area showed that lysozyme-binding cavity was more exposed to the surface as compared to the other two proteins. Free energy analysis of all protein systems showed the stability of protein-benzoic acid complexes with lysozyme and BSA relatively more stable than zein system. The results of our study provided important insights to the dynamic and structural information about protein-benzoic acid interactions with BSA, zein and lysozyme proteins. This work is important in enhancing the stability of therapeutic protein drugs loaded on carboxyl substrates.