Pharmacoinformatic approach to identify potential phytochemicals against SARS-CoV-2 spike receptor-binding domain in native and variants of concern.

Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) pathogenesis is initiated by the binding of SARS-CoV-2 spike (S) protein with the angiotensin-converting enzyme 2 receptor (ACE2R) on the host cell surface. The receptor-binding domain (RBD) of the S protein mediates the binding and is more prone to mutations resulting in the generation of different variants. Recently, molecules with the potential to inhibit the interaction of S protein with ACE2R have been of interest due to their therapeutic value. In this context, the present work was performed to identify potential RBD binders from the Indian medicinal plant's phytochemical database through virtual screening, molecular docking, and molecular dynamic simulation. Briefly, 1578 compounds filtered from 9596 phytochemicals were chosen for screening against the RBD of the native SARS-CoV-2 S protein. Based on the binding energy, the top 30 compounds were selected and re-docked individually against the native and five variants of concern (VOCs: alpha, beta, gamma, delta, and omicron) of SARS-CoV-2. Four phytochemicals, namely withanolide F, serotobenine, orobanchol, and gibberellin A51, were found to be potential RBD binders in native and all SARS-CoV-2 VOCs. Among the four, withanolide F exhibited lower binding energy (- 10.84 to - 8.56 kcal/mol) and better ligand efficiency (- 0.3 to - 0.25) against all forms of RBD and hence was subjected to a 100 ns MD simulation which confirmed its stringent binding to the RBDs in native and VOCs. The study prioritizes withanolide F as a prospective COVID-19 (Coronavirus disease) therapeutic agent based on the observations. It warrants deeper investigations into the four promising leads for understanding their precise therapeutic value.

Improved Binding Affinity of Omicron's Spike Protein for the Human Angiotensin-Converting Enzyme 2 Receptor Is the Key behind Its Increased Virulence.

The new variant of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), Omicron, has been quickly spreading in many countries worldwide. Compared to the original virus, Omicron is characterized by several mutations in its genomic region, including the spike protein's receptor-binding domain (RBD). We have computationally investigated the interaction between the RBD of both the wild type and Omicron variant of SARS-CoV-2 with the human angiotensin-converting enzyme 2 (hACE2) receptor using molecular dynamics and molecular mechanics-generalized Born surface area (MM-GBSA)-based binding free energy calculations. The mode of the interaction between Omicron's RBD with the hACE2 receptor is similar to the original SARS-CoV-2 RBD except for a few key differences. The binding free energy difference shows that the spike protein of Omicron has an increased affinity for the hACE2 receptor. The mutated residues in the RBD showed strong interactions with a few amino acid residues of hACE2. More specifically, strong electrostatic interactions (salt bridges) and hydrogen bonding were observed between R493 and R498 residues of the Omicron RBD with D30/E35 and D38 residues of the hACE2, respectively. Other mutated amino acids in the Omicron RBD, e.g., S496 and H505, also exhibited hydrogen bonding with the hACE2 receptor. A pi-stacking interaction was also observed between tyrosine residues (RBD-Tyr501: hACE2-Tyr41) in the complex, which contributes majorly to the binding free energies and suggests that this is one of the key interactions stabilizing the formation of the complex. The resulting structural insights into the RBD:hACE2 complex, the binding mode information within it, and residue-wise contributions to the free energy provide insight into the increased transmissibility of Omicron and pave the way to design and optimize novel antiviral agents.

Effect of COVID-19 on 18F-FDG PET/CT: Is There a Need to Consider COVID-19 Status Before Planning 18F-FDG PET/CT for Oncologic Evaluation?

Incidental detection of coronavirus disease 2019 (COVID-19)-related lung changes on 18F-FDG PET/CT images of oncology patients has been increasingly reported. Most of the case reports or series have stressed the retrospective diagnosis of COVID-19 with the help of 18F-FDG PET/CT lung findings. In this case report, we introduce a different aspect of COVID-19-related lung changes on 18F-FDG PET/CT, interfering with the evaluation of metastatic lung lesions in a patient with renal cell carcinoma.

Structure-Based Virtual Screening to Discover Potential Lead Molecules for the SARS-CoV-2 Main Protease.

The COVID-19 disease is caused by a new strain of the coronavirus family (SARS-CoV-2), and it has affected at present millions of people all over the world. The indispensable role of the main protease (Mpro) in viral replication and gene expression makes this enzyme an attractive drug target. Therefore, inhibition of SARS-CoV-2 Mpro as a proposition to halt virus ingression is being pursued by scientists globally. Here we carried out a study with two objectives: the first being to perform comparative protein sequence and 3D structural analysis to understand the effect of 12 point mutations on the active site. Among these, two mutations, viz., Ser46 and Phe134, were found to cause a significant change at the active sites of SARS-CoV-2. The Ser46 mutation present at the entrance of the S5 subpocket of SARS-CoV-2 increases the contribution of other two hydrophilic residues, while the Phe134 mutation, present in the catalytic cysteine loop, can cause an increase in catalytic efficiency of Mpro by facilitating fast proton transfer from the Cys145 to His41 residue. It was observed that active site remained conserved among Mpro of both SARS-CoVs, except at the entrance of the S5 subpocket, suggesting sustenance of substrate specificity. The second objective was to screen the inhibitory effects of three different data sets (natural products, coronaviruses main protease inhibitors, and FDA-approved drugs) using a structure-based virtual screening approach. A total of 73 hits had a combo score >2.0. Eight different structural scaffold classes were identified, such as one/two tetrahydropyran ring(s), dipeptide/tripeptide/oligopeptide, large (approximately 20 atoms) cyclic peptide, and miscellaneous. The screened hits showed key interactions with subpockets of the active site. Further, molecular dynamics studies of selected screened compounds confirmed their perfect fitting into the subpockets of the active site. This study suggests promising structures that can fit into the SARS-CoV-2 Mpro active site and also offers direction for further lead optimization and rational drug design.