Browsing by Author "Swai, Hulda S."

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    Abrogating the nsp10–nsp16 switching mechanisms in SARS-CoV-2 by phytochemicals from Withania somnifera: a molecular dynamics study
    (Taylor & Francis, 2021) Vuai, Said A. H.; Onokaa, Isaac; Sahini, Mtabazi G.; Swai, Hulda S.; Shadrack, Daniel M.
    The search for therapeutic small molecules and vaccines for Covid-19 treatment is an urgent but evolving topic. The virus has claimed over 3,782,490 lives (as of 12 June 2021), with the figure expected to rise due to the high versatility of the SAR-CoV-2 variant. Therapeutic options based on SARS-CoV-2 inhibitor are essential. Withanolides have a long history in traditional medicines with versatile biological properties including antiviral activities. In this study, the inhibitory potential of withanolides from Withania somnifera (Ashwagandha) against SARS-CoV-2 non-structural protein 10 (nsp10) was investigated by employing atomistic in silico methods viz molecular docking, molecular dynamics and binding free energy calculations. Investigated Withania somnifera compounds demonstrated binding affinity to the nsp10 and in its complex form, that is, nsp10-nsp16 heterodimer. Two withanolides; withanoside IV and withanoside V isolated from the roots of Withania somnifera demonstrated strong inhibition with binding free energies of −29.5 and −29.1 kJ/mol, respectively. Molecular dynamics and binding free energy ascertained the stability of withanoside IV. Water molecules, although known to play an important role in mediating biological systems, herein, water was found to have a repulsive binding effect to some residues, suggesting that the binding of withanoside IV would require dewetting of the nsp10 or displacing the water to bulk solvents. Interestingly, residues in the nsp10 that are responsible for forming stable interaction at the nsp10–nsp16 were found to be strongly interacting with withanoside IV, hence weakening the nsp10–nsp16 interaction and recognition. Further in vitro and in vivo experiments are recommended to validate the anti-SARS-COV-2 potential of these phytochemicals.
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    Abrogating the nsp10–nsp16 switching mechanisms in SARS-CoV-2 by phytochemicals from Withania somnifera: a molecular dynamics study
    (Taylor & Francis, 2021) Vuai, Said A. H.; Onoka, Isaac; Sahini, Mtabazi G.; Swai, Hulda S.; Shadrack, Daniel M.
    The search for therapeutic small molecules and vaccines for Covid-19 treatment is an urgent but evolving topic. The virus has claimed over 3,782,490 lives (as of 12 June 2021), with the figure expected to rise due to the high versatility of the SAR-CoV-2 variant. Therapeutic options based on SARS-CoV-2 inhibitor are essential. Withanolides have a long history in traditional medicines with versatile biological properties including antiviral activities. In this study, the inhibitory potential of withanolides from Withania somnifera (Ashwagandha) against SARS-CoV-2 non-structural protein 10 (nsp10) was investigated by employing atomistic in silico methods viz molecular docking, molecular dynamics and binding free energy calculations. Investigated Withania somnifera compounds demonstrated binding affinity to the nsp10 and in its complex form, that is, nsp10-nsp16 heterodimer. Two withanolides; withanoside IV and withanoside V isolated from the roots of Withania somnifera demonstrated strong inhibition with binding free energies of −29.5 and −29.1 kJ/mol, respectively. Molecular dynamics and binding free energy ascertained the stability of withanoside IV. Water molecules, although known to play an important role in mediating biological systems, herein, water was found to have a repulsive binding effect to some residues, suggesting that the binding of withanoside IV would require dewetting of the nsp10 or displacing the water to bulk solvents. Interestingly, residues in the nsp10 that are responsible for forming stable interaction at the nsp10–nsp16 were found to be strongly interacting with withanoside IV, hence weakening the nsp10–nsp16 interaction and recognition. Further in vitro and in vivo experiments are recommended to validate the anti-SARS-COV-2 potential of these phytochemicals.
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    Relaxed complex scheme and molecular dynamics simulation suggests small molecule inhibitor of human TMPRSS2 for combating COVID-19
    (Taylor & Francis, 2021) Vuai, Said A. H.; Ogedjo, Marcelina M.; Isaac, Onoka; Sahini, Mtabazi G.; Swai, Hulda S.; Shadrack, Daniel M.
    As the coronavirus disease 19 (COVID-19) pandemic continues to pose a health and economic crisis worldwide, the quest for drugs and/or vaccines against the virus continues. The human transmembrane protease serine 2 (TMPRSS2) has attracted attention as a target for drug discovery, as inhibition of its catalytic reaction would result in the inactivation of the proteolytic cleavage of the SARS-CoV-2 S protein. As a result, the inactivation prevents viral cell entry to the host’s cell. In this work, we screened and identified two potent molecules that interact and inhibit the catalytic reaction by using computational approaches. Two docking screening experiments were performed utilizing the crystal structure and holo ensemble structure obtained from molecular dynamics in bound form. There is enhancement and sensitivity of docking results to the holo ensemble as compared to the crystal structure. Compound 1 demonstrated a similar inhibition value to nafamostat by interacting with catalytic triad residues His296 and Ser441, thereby disrupting the already established hydrogen bond interaction. The stability of the ligand–TMPRSS2 complexes was studied by molecular dynamics simulation, and the binding energy was re-scored by using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy. The obtained compounds may serve as an initial point toward the discovery of potent TMPRSS2 inhibitors upon further in vivo validation.