No abstract

Several viruses of the corona family interact, via their spike (S) proteins, with human cellular receptors. Spike proteins of SARS-CoV-1 and SARS-CoV-2 virions, being structurally related but not identical, mediate attachment to the human angiotensin-converting enzyme 2 (hACE2) receptor in similar but non-identical ways. Molecular-level understanding of interactions between spike proteins and hACE2 can aid strategies for blocking attachment of SARS-CoV-1, a potentially reemerging health threat, to human cells. We have identified dominant molecular-level interactions, some attractive and some repulsive, between the receptor binding domain of SARS-CoV-1 spike proteins (S-RBD) and hACE2. We performed fragment-based quantum-biochemical calculations which directly relate biomolecular structure to the hACE2...S-RBD interaction energy. Consistent with X-ray crystallography and cryo-EM, the interaction energy between hACE2 and S-RBD ($$\approx -$$ ≈ - 26 kcal/mol) corresponds to a net intermolecular attraction which is significantly enhanced by inclusion of dispersion van der Waals forces. Protein fragments at the hACE2...S-RBD interface, that dominate host-virus attraction, have been identified together with their constituent amino acid residues. Two hACE2 fragments which include residues (GLU37, ASP38, TYR41, GLN42) and (GLU329, LYS353, GLY354), respectively, as well as three S-RBD fragments which include residues (TYR436), (ARG426) and (THR487, GLY488, TYR491), respectively, have been identified as primary attractors at the hACE2...S-RBD interface.

No abstract

The recent pandemic caused by SARS-CoV-2 has led the world to a standstill, causing a medical and economic crisis worldwide. This crisis has triggered an urgent need to discover a possible treatment strategy against this novel virus using already-approved drugs. The main protease (Mpro) of this virus plays a critical role in cleaving the translated polypeptides that makes it a potential drug target against COVID-19. Taking advantage of the recently discovered three-dimensional structure of Mpro, we screened approved drugs from the Drug Bank to find a possible inhibitor against Mpro using computational methods and further validating them with biochemical studies. The docking and molecular dynamics study revealed that DB04983 (denufosol) showed the best glide docking score, −11.884 kcal/mol, and MM-PBSA binding free energy, −10.96 kcal/mol. Cobicistat, cangrelor (previous computational studies in our lab), and denufosol (current study) were tested for the in vitro inhibitory effects on Mpro. The IC 50 values of these drugs were ∼6.7 μM, 0.9 mM, and 1.3 mM, respectively, while the values of dissociation constants calculated using surface plasmon resonance were ∼2.1 μM, 0.7 mM, and 1.4 mM, respectively. We found that cobicistat is the most efficient inhibitor of Mpro both in silico and in vitro. In conclusion, cobicistat, which is already an FDA-approved drug being used against HIV, may serve as a good inhibitor against the main protease of SARS-CoV-2 that, in turn, can help in combating COVID-19, and these results can also form the basis for the rational structure-based drug design against COVID-19.

Clostridioides difficile is the most common cause of healthcare-associated diarrhea. Disease complications as well as recurrent infections contribute significantly to morbidity and mortality. Over the past decades, there has been a rapid increase in the incidence of C. difficile infection (CDI), with a rise in the number of community-acquired cases. CDI has a profound economic impact on both the healthcare system and patients, secondary to recurrences, hospitalization, prolonged length of stay, cost of treatment, and indirect societal costs. With emergence of newer treatment options, the standard of care is shifting from metronidazole and vancomycin towards fidaxomicin and fecal microbiota transplantation (FMT), which despite being more expensive, are more efficacious in preventing recurrences and hence overall are more beneficial forms of therapy per cost-effectiveness analyses. Data regarding preferred route of FMT, timing of FMT, and non-conventional therapies such as bezlotoxumab is scant. There is a need for further studies to elucidate the true attributable costs of CDI as well as continued cost-effectiveness research to reduce the economic burden associated with the disease and improve clinical practice.