Evaluation of phytoconstituents of Tinospora cordifolia against K417N and N501Y mutant spike glycoprotein and main protease of SARS-CoV-2- an in silico study.

Coronavirus disease 2019 (COVID-19) caused appalling conditions over the globe, which is currently faced by the entire human population. One of the primary reasons behind the uncontrollable situation is the lack of specific therapeutics. In such conditions, drug repurposing of available drugs (viz. Chloroquine, Lopinavir, etc.) has been proposed, but various clinical and preclinical investigations indicated the toxicity and adverse side effects of these drugs. This study explores the inhibition potency of phytochemicals from Tinospora cordifolia (Giloy) against SARS CoV-2 drugable targets (spike glycoprotein and Mpro proteins) using molecular docking and MD simulation studies. ADMET, virtual screening, MD simulation, postsimulation analysis (RMSD, RMSF, Rg, SASA, PCA, FES) and MM-PBSA calculations were carried out to predict the inhibition efficacy of the phytochemicals against SARS CoV-2 targets. Tinospora compounds showed better binding affinity than the corresponding reference. Their binding affinity ranges from -9.63 to -5.68 kcal/mole with spike protein and -10.27 to -7.25 kcal/mole with main protease. Further 100 ns exhaustive simulation studies and MM-PBSA calculations supported favorable and stable binding of them. This work identifies Nine Tinospora compounds as potential inhibitors. Among those, 7-desacetoxy-6,7-dehydrogedunin was found to inhibit both spike (7NEG) and Mpro (7MGS and 6LU7) proteins, and Columbin was found to inhibit selected spike targets (7NEG and 7NX7). In all the analyses, these compounds performed well and confirms the stable binding. Hence the identified compounds, advocated as potential inhibitors can be taken for further in vitro and in vivo experimental validation to determine their anti-SARS-CoV-2 potential.Communicated by Ramaswamy H. Sarma.

The cross-talk between mucormycosis, steroids and diabetes mellitus amidst the global contagion of COVID-19.

Mucormycosis is an opportunistic fungal disease that targets individuals having an impaired immune system due to a wide array of risk factors including HIV-AIDS, immunosuppressive therapy, diabetes mellitus, etc. The current explosive outbreak of coronavirus disease 2019 (COVID-19) has become the latest threat to such patients who are already susceptible to secondary infections. Physiological outcomes of COVID-19 end up in a cascade of grave alterations to the immunological profile and irreparable harm to their respiratory passage, heart and kidneys. Corticosteroidal treatment facilitates faster recovery and alleviates the adverse pathological effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). But clinical reports lend this approach a darker perspective especially if these patients have pre-existing diabetes mellitus. The mucormycotic fungal genera belonging to the order Mucorales not only survive but thrive under the comorbidity of COVID-19 and diabetes, often staying undetected until they have inflicted irreversible damage. Steroidal usage has been noted to be a common thread in the sudden spurt in secondary fungal infections among COVID-19 cases. Once considered a rare occurrence, mucormycosis has now acquired a notoriously lethal status in mainstream medical hierarchy. We set out to investigate whether corticosteroidal therapy against COVID-19 emboldens the development of mucormycosis. We also assess the conditions brought forth by steroidal usage and uncontrolled progression of diabetes in COVID-19 cases and their effect on the susceptibility towards mucormycosis.