Understanding the activating mechanism of the immune system against COVID-19 by Traditional Indian Medicine: Network pharmacology approach.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmissions are occurring rapidly; it is raising the alarm around the globe. Though vaccines are currently available, the evolution and mutations in the SARS-CoV-2 threaten available vaccines' significance. The drugs are still undergoing clinical trials, and certain medications are approved for "emergency use" or as an "off-label" drug during the pandemic. These drugs have been effective yet accommodating side effects, which also can be lethal. Complementary and alternative medicine is highly demanded since it embraces a holistic approach. Since ancient times, natural products have been used as drugs to treat various diseases in the medical field and are still widely practiced. Medicinal plants contain many active compounds that serve as the key to an effective drug design. The Kabasura kudineer and Nilavembu kudineer are the two most widely approved formulations to treat COVID-19. However, the mechanism of these formulations is not well known. The proposed study used a network pharmacology approach to understand the immune-boosting mechanism by the Kabasura kudineer, Nilavembu kudineer, and JACOM in treating COVID-19. The plants and phytochemical chemical compounds in the Kabasura kudineer, Nilavembu kudineer, and JACOM were obtained from the literature. The Swiss target prediction algorithm was used to predict the targets for these phytochemical compounds. The common genes for the COVID-19 infection and the drug targets were identified. The gene-gene interaction network was constructed to understand the interactions between these common genes and enrichment analyses to determine the biological process, molecular functions, cellular functions, pathways involved, etc. Finally, virtual screening and molecular docking studies were performed to identify the most potential targets and significant phytochemical compounds to treat the COVID-19. The present study identified potential targets as ACE, Cathepsin L, Cathepsin B, Cathepsin K, DPP4, EGFR, HDAC2, IL6, RIPK1, and VEGFA. Similarly, betulinic acid, 5″-(2⁗-Hydroxybenzyl) uvarinol, antofine, (S)-1'-methyloctyl caffeate, (Z)-3-phenyl-2-propenal, 7-oxo-10α-cucurbitadienol, and PLX-4720 collectively to be potential treatment agents for COVID-19.

Computational model to analyze and characterize the functional mutations of NOD2 protein causing inflammatory disorder - Blau syndrome.

Blau syndrome (BS), which affects the eyes, skin, and joints, is an autosomal dominant genetic inflammatory disorder. BS is caused by mutations in the NOD2 gene. However, there are no direct treatments, and treatment with conventional anti-inflammatory drugs such as adrenal glucocorticoids, anti-metabolites, and biological agents such as anti-TNF and infliximab have all been attempted with varying degrees of success. In this study, we tried to identify all the reported mutations in the NOD2 protein that cause BS. Collectively, 114 missense mutations were extracted from the UniProt, ClinVar, and HGMD databases. The mutations were further subjected to pathogenic, stability, and conservation analyses. According to these computational analyses, six missense mutations (R334Q, R334W, E383G, E383K, R426H, and T605P) were found to be highly deleterious, destabilizing, and positioned in the conserved position. ADP to ATP conversion plays a crucial role in switching the closed-form of NOD2 protein to the open-form, thus activating the protein. Accordingly, the mutations in the ADP binding sites have received more attention in comparison to the mutations in the non-ADP binding positions. Interestingly, the W490L mutation is positioned in the ADP binding site and exhibits highly deleterious and destabilizing properties. Additionally, W490L was also found to be conserved, with a ConSurf score of 7. Therefore, we further performed homology modeling to determine the 3D structure of native NOD2 and the W490L mutant. Molecular docking analysis was carried out to understand the change in the interaction of ADP with the NOD2 protein. We observed that ADP had a stronger interaction with the native NOD2 protein compared to the W490L mutant. Finally, ADP complexed with native NOD2 and W490L mutant were subjected to molecular dynamics simulations, and the trajectories were analyzed. In the simulations, we observed decreased deviation and fluctuations in native NOD2, whereas decreased compactness and inter- and intramolecular hydrogen bonds were observed in the W490L mutant. This study is expected to serve as a platform for developing targeted drug therapy for BS.