Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction

Since SARS-CoV-2 Omicron variant (B.1.1.529) was reported in November 2021, it has quickly spread to many countries and outcompeted the globally dominant Delta variant in several countries. The Omicron variant contains the largest number of mutations to date, with 32 mutations located at spike (S) glycoprotein, which raised great concern for its enhanced viral fitness and immune escape[1-4]. In this study, we reported the crystal structure of the receptor binding domain (RBD) of Omicron variant S glycoprotein bound to human ACE2 at a resolution of 2.6 Å. Structural comparison, molecular dynamics simulation and binding free energy calculation collectively identified four key mutations (S477N, G496S, Q498R and N501Y) for the enhanced binding of ACE2 by the Omicron RBD compared to the WT RBD. Representative states of the WT and Omicron RBD-ACE2 systems were identified by Markov State Model, which provides a dynamic explanation for the enhanced binding of Omicron RBD. The effects of the mutations in the RBD for antibody recognition were analyzed, especially for the S371L/S373P/S375F substitutions significantly changing the local conformation of the residing loop to deactivate several class IV neutralizing antibodies.

Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction

Since SARS-CoV-2 Omicron variant (B.1.1.529) was reported in November 2021, it has quickly spread to many countries and outcompeted the globally dominant Delta variant in several countries. The Omicron variant contains the largest number of mutations to date, with 32 mutations located at spike (S) glycoprotein, which raised great concern for its enhanced viral fitness and immune escape[1-4]. In this study, we reported the crystal structure of the receptor binding domain (RBD) of Omicron variant S glycoprotein bound to human ACE2 at a resolution of 2.6 angstrom. Structural comparison, molecular dynamics simulation and binding free energy calculation collectively identified four key mutations (S477N, G496S, Q498R and N501Y) for the enhanced binding of ACE2 by the Omicron RBD compared to the WT RBD. Representative states of the WT and Omicron RBD-ACE2 systems were identified by Markov State Model, which provides a dynamic explanation for the enhanced binding of Omicron RBD. The effects of the mutations in the RBD for antibody recognition were analyzed, especially for the S371L/S373P/S375F substitutions significantly changing the local conformation of the residing loop to deactivate several class IV neutralizing antibodies.

Assessment of Activity of Chalcone Compounds as Inhibitors of 3-Chymotrypsin Like Protease (3CLPro) of SARS-CoV-2: in Silico Study

The COVID-19 is still pandemic due to emerging of the various variant of concern of SARS-CoV2. Hence it is devastating the world, causing significant economic as well as social chaos. This needs great effort to search and develop effective alternatives along with vaccination. Therefore to continue drug discovery endeavors, we used chalcone derivatives to find an effective drug candidate against SARS-CoV2. Chalcone is a common simple scaffold that exists in many diets as well as in traditional medicine. Natural as well as synthetic chalcones have shown numerous interesting biological activities and are also effective in fighting various diseases. Hence various computational methods were applied to find out potential inhibitors of 3CLPro using a library of 3000 compounds of chalcones. Firstly the screening by structure-based pharmacophore model yielded 84 hits that were subjected to molecular docking. The top 10 docked compounds were characterized for stability by using 100 nanoseconds (ns) molecular dynamic (MD) simulation approach. Further, the binding free energy calculation by MMPBSA showed that four compounds bind to 3CLPro enzyme with high affinity i.e., -87.962(KJ/mol), -66.125 (KJ/mol), -59.589(KJ/mol), and -66.728(KJ/mol) respectively. Since chalcone is a common simple scaffold that is present in many diets as well as in traditional medicine, we suggest that screened compounds may emerge as promising drug candidates for SARS-CoV-2. These compounds may be investigated in vitro to evaluate the efficacy againstSARS-CoV-2.

Identifying the Hot Spot Residues of the SARS-CoV-2 Main Protease Using MM-PBSA and Multiple Force Fields

In this study, we investigated the binding affinities between the main protease of SARS-CoV-2 virus (Mpro) and its various ligands to identify the hot spot residues of the protease. To benchmark the influence of various force fields on hot spot residue identification and binding free energy calculation, we performed MD simulations followed by MM-PBSA analysis with three different force fields: CHARMM36, AMBER99SB, and GROMOS54a7. We performed MD simulations with 100 ns for 11 protein–ligand complexes. From the series of MD simulations and MM-PBSA calculations, it is identified that the MM-PBSA estimations using different force fields are weakly correlated to each other. From a comparison between the force fields, AMBER99SB and GROMOS54a7 results are fairly correlated while CHARMM36 results show weak or almost no correlations with the others. Our results suggest that MM-PBSA analysis results strongly depend on force fields and should be interpreted carefully. Additionally, we identified the hot spot residues of Mpro, which play critical roles in ligand binding through energy decomposition analysis. It is identified that the residues of the S4 subsite of the binding site, N142, M165, and R188, contribute strongly to ligand binding. In addition, the terminal residues, D295, R298, and Q299 are identified to have attractive interactions with ligands via electrostatic and solvation energy. We believe that our findings will help facilitate developing the novel inhibitors of SARS-CoV-2.

In Silico Screening of Available Drugs Targeting Non-Small Cell Lung Cancer Targets: A Drug Repurposing Approach

The RAS–RAF–MEK–ERK pathway plays a key role in malevolent cell progression in many tumors. The high structural complexity in the upstream kinases limits the treatment progress. Thus, MEK inhibition is a promising strategy since it is easy to inhibit and is a gatekeeper for the many malignant effects of its downstream effector. Even though MEK inhibitors are under investigation in many cancers, drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. Hence, we accomplished a high-throughput virtual screening to overcome this bottleneck by the discovery of dual-targeting therapy in cancer treatment. Here, a total of 11,808 DrugBank molecules were assessed through high-throughput virtual screening for their activity against MEK. Further, the Glide docking, MLSF and prime-MM/GBSA methods were implemented to extract the potential lead compounds from the database. Two compounds, DB012661 and DB07642, were outperformed in all the screening analyses. Further, the study results reveal that the lead compounds also have a significant binding capability with the co-target PIM1. Finally, the SIE-based free energy calculation reveals that the binding of compounds was majorly affected by the van der Waals interactions with MEK receptor. Overall, the in silico binding efficacy of these lead compounds against both MEK and PIM1 could be of significant therapeutic interest to overcome drug resistance in the near future.

Turning C1-gases to Isobutanol Towards a Great Environmental and Economic Sustainability via Innovative Biological Routes: Two Birds With One Stone

BackgroundThe dramatic increase in emissions of greenhouse gases (GHGs) has led to an irreversible effect on the ecosystem, which in turn caused significant harm to human beings and other species. Exploring innovative and effective approaches to neutralizing GHGs is urgently needed. Considering the advancement of synthetic biology and the bioconversion process, C1-utilizing cell factories (CUCFs) have been modified to be able to effectively convert C1-gases includes biogas, natural gas, and carbon dioxide (CO2) into chemicals or fuels via biological routes, which greatly facilitates the inedible carbon sources used in biomanufacturing, increases the potential value of GHGs and meanwhile reduces the GHG emissions. Process design and resultsEven though the current experimental results are satisfactory in lab-scale research, the evaluation of economic feasibility as well as applications of CUCFs in industrial-scale still need to be analyzed. This study designed three scenarios of CUCFs-based conversion of biogas, natural gas, and CO2 into isobutanol, the detailed techno-economic analyses of these scenarios were conducted with the comparisons of capital cost, operating cost, and minimum isobutanol selling price (MISP). Results revealed that direct bio-conversion of CO2 by CUCFs into isobutanol exhibited the best economic performance with a MISP of $1.38/kg isobutanol. The single sensitivity analysis showed that the gas utilization rate, flow rate, and CO2 cost are the three most significant economic-driving forces on MISP of CO2-derived biological isobutanol. Multiple-point sensitivity analysis presented that the MISP for the long-term case can be as low as 0.99 $/kg with using ideal targets. ConclusionsOur findings provide a comprehensive assessment of bio-conversion of C1-gases via CUCFs to isobutanol in terms of the bioprocess design, mass/energy calculation, capital investment, operating expense, sensitivity analysis, and environmental impact. It is expected that this study may lead to the paradigm shift in isobutanol synthesis with C1-gases as substrates.

Computational Insights Into the Effects of the R190K and N121Q Mutations on the SARS-CoV-2 Spike Complex With Biliverdin

The SARS-CoV-2 spike has been regarded as the main target of antibody design against COVID-19. Two single-site mutations, R190K and N121Q, were deemed to weaken the binding affinity of biliverdin although the underlying molecular mechanism is still unknown. Meanwhile, the effect of the two mutations on the conformational changes of “lip” and “gate” loops was also elusive. Thus, molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation were conducted on the wild-type and two other SARS-CoV-2 spike mutants. Our simulations indicated that the R190K mutation causes Lys190 to form six hydrogen bonds, guided by Asn99 and Ile101, which brings Lys190 closer to Arg102 and Asn121, thereby weakening the interaction energy between biliverdin and Ile101 as well as Lys190. For the N121Q mutation, Gln121 still maintained a hydrogen bond with biliverdin; nevertheless, the overall binding mode deviated significantly under the reversal of the side chain of Phe175. Moreover, the two mutants would stabilize the lip loop, which would restrain the meaningful upward movement of the lip. In addition, N121Q significantly promoted the gate loop deviating to the biliverdin binding site and compressed the site. This work would be useful in understanding the dynamics binding biliverdin to the SARS-CoV-2 spike.