Identification of potential inhibitors of omicron variant of SARS-Cov-2 RBD based virtual screening, MD simulation, and DFT

Emergence of the SARS-CoV-2 Omicron variant of concern (VOC; B.1.1.529) resulted in a new peak of the COVID-19 pandemic, which called for development of effective therapeutics against the Omicron VOC. The receptor binding domain (RBD) of the spike protein, which is responsible for recognition and binding of the human ACE2 receptor protein, is a potential drug target. Mutations in receptor binding domain of the S-protein have been postulated to enhance the binding strength of the Omicron VOC to host proteins. In this study, bioinformatic analyses were performed to screen for potential therapeutic compounds targeting the omicron VOC. A total of 92,699 compounds were screened from different libraries based on receptor binding domain of the S-protein via docking and binding free energy analysis, yielding the top 5 best hits. Dynamic simulation trajectory analysis and binding free energy decomposition were used to determine the inhibitory mechanism of candidate molecules by focusing on their interactions with recognized residues on receptor binding domain. The ADMET prediction and DFT calculations were conducted to determine the pharmacokinetic parameters and precise chemical properties of the identified molecules. The molecular properties of the identified molecules and their ability to interfere with recognition of the human ACE2 receptors by receptor binding domain suggest that they are potential therapeutic agents for SARS-CoV-2 Omicron VOC

Single-particle coal ignition and alkali metal radiation characteristics based on optical diagnosis technology

Study on the ignition characteristics of coal is the theoretical basis for realizing the high-efficient and clean utilization of coal. The alkali metals such as K and Na in coal are released into the gas phase during combustion and enter the system, which can easily cause high temperature corrosion of the reactor, fouling of the heating surface and slagging in the furnace. Based on the single-particle coal ignition detection platform, the ignition and alkali metal Na* and K* radiation characteristics of single-particle Yangchangwan (YCW) bituminous coal and Naomaohu (NMH) lignite during combustion were investigated under different oxygen volume flow rates. High-speed camera technology was used to capture the flame evolution process during single-particle coal ignition, and hyperspectral imaging technology was used to measure the spontaneous emission spectra of alkali metals Na* and K* in the flame to obtain the spatial release behavior of alkali metals. The results show that the ignition process of different types of coal is different. The enveloping flame is formed in the combustion process of volatile matter in the YCW coal particles, while the ignition reaction of the NMH coal is more intense without enveloping phenomenon due to its high volatile matter content, and the flame brightness in the whole ignition process is stronger than that of the YCW coal. The increase of oxygen can promote the ignition of coal particles, with the increase of oxygen volume flow, the ignition delay time of the YCW coal and the NMH coal decreases, and the ignition delay time of the NMH coal is smaller than that of the YCW coal. When the fire occurs, the flame brightness is the brightest, and the flame shape is relatively smooth and stable. The radiation characteristics of alkali metals Na* and K* in single-particle YCW coal and NMH coal during ignition and combustion are different from that in coke combustion process, in which the radiation intensity of Na* and K* is the strongest. Na* has a release peak both in the volatile reaction process and coke reaction process, but K* radiation intensity does not have an obvious release peak in the volatile reaction process and coke combustion process. When oxygen content increases, the release time of alkali metals from the YCW coal and the NMH coal is gradually advanced, and the beginning time of alkali metal radiation from the NMH coal is less than that from the YCW coal. In addition, the analysis of the ignition process of single-particle coal shows that the release intensity of alkali metals Na* and K* in the peripheral position of the combustion flame is stronger than that in the central position

Computational design of α-amylase from Bacillus licheniformis to increase its activity and stability at high temperatures

The thermostable α-amylase derived from Bacillus licheniformis (BLA) has multiple advantages, including enhancing the mass transfer rate and by reducing microbial contamination in starch hydrolysis. Nonetheless, the application of BLA is constrained by the accessibility and stability of enzymes capable of achieving high conversion rates at elevated temperatures. Moreover, the thermotolerance of BLA requires further enhancement. Here, we developed a computational strategy for constructing small and smart mutant libraries to identify variants with enhanced thermostability. Initially, molecular dynamics (MD) simulations were employed to identify the regions with high flexibility. Subsequently, FoldX, a computational design predictor, was used to design mutants by rigidifying highly flexible residues, whereas the simultaneous decrease in folding free energy assisted in improving thermostability. Through the utilization of MD and FoldX, residues K251, T277, N278, K319, and E336, situated at a distance of 5 Å from the catalytic triad, were chosen for mutation. Seventeen mutants were identified and characterized by evaluating enzymatic characteristics and kinetic parameters. The catalytic efficiency of the E271L/N278K mutant reached 184.1 g L−1 s−1, which is 1.88-fold larger than the corresponding value determined for the WT. Furthermore, the most thermostable mutant, E336S, exhibited a 1.43-fold improvement in half-life at 95 ℃, compared with that of the WT. This study, by combining computational simulation with experimental verification, establishes that potential sites can be computationally predicted to increase the activity and stability of BLA and thus provide a possible strategy by which to guide protein design

DataSheet2_Identification of potential inhibitors of omicron variant of SARS-Cov-2 RBD based virtual screening, MD simulation, and DFT.docx

Emergence of the SARS-CoV-2 Omicron variant of concern (VOC; B.1.1.529) resulted in a new peak of the COVID-19 pandemic, which called for development of effective therapeutics against the Omicron VOC. The receptor binding domain (RBD) of the spike protein, which is responsible for recognition and binding of the human ACE2 receptor protein, is a potential drug target. Mutations in receptor binding domain of the S-protein have been postulated to enhance the binding strength of the Omicron VOC to host proteins. In this study, bioinformatic analyses were performed to screen for potential therapeutic compounds targeting the omicron VOC. A total of 92,699 compounds were screened from different libraries based on receptor binding domain of the S-protein via docking and binding free energy analysis, yielding the top 5 best hits. Dynamic simulation trajectory analysis and binding free energy decomposition were used to determine the inhibitory mechanism of candidate molecules by focusing on their interactions with recognized residues on receptor binding domain. The ADMET prediction and DFT calculations were conducted to determine the pharmacokinetic parameters and precise chemical properties of the identified molecules. The molecular properties of the identified molecules and their ability to interfere with recognition of the human ACE2 receptors by receptor binding domain suggest that they are potential therapeutic agents for SARS-CoV-2 Omicron VOC.</p

DataSheet1_Identification of potential inhibitors of omicron variant of SARS-Cov-2 RBD based virtual screening, MD simulation, and DFT.CSV

Emergence of the SARS-CoV-2 Omicron variant of concern (VOC; B.1.1.529) resulted in a new peak of the COVID-19 pandemic, which called for development of effective therapeutics against the Omicron VOC. The receptor binding domain (RBD) of the spike protein, which is responsible for recognition and binding of the human ACE2 receptor protein, is a potential drug target. Mutations in receptor binding domain of the S-protein have been postulated to enhance the binding strength of the Omicron VOC to host proteins. In this study, bioinformatic analyses were performed to screen for potential therapeutic compounds targeting the omicron VOC. A total of 92,699 compounds were screened from different libraries based on receptor binding domain of the S-protein via docking and binding free energy analysis, yielding the top 5 best hits. Dynamic simulation trajectory analysis and binding free energy decomposition were used to determine the inhibitory mechanism of candidate molecules by focusing on their interactions with recognized residues on receptor binding domain. The ADMET prediction and DFT calculations were conducted to determine the pharmacokinetic parameters and precise chemical properties of the identified molecules. The molecular properties of the identified molecules and their ability to interfere with recognition of the human ACE2 receptors by receptor binding domain suggest that they are potential therapeutic agents for SARS-CoV-2 Omicron VOC.</p

SUMOylation Regulates BmNPV Replication by Moderating PKIP Intracellular Localization

SUMOylation is a reversible covalent process between a small ubiquitin-like modifier (SUMO) and its target protein and has become a crucial regulator of protein functions. Here, we report that Bombyx mori nucleopolyhedrovirus (BmNPV) may take advantage of the host SUMOylation system to enhance its own replication, similar to many other viruses. Both the knockdown of BmSUMO by RNAi and chemical blocking by ginkgolic acid both impaired BmNPV replication. Using site mutation and pull-down assays, we found that lysine K70 of the protein kinase-interacting protein (PKIP), which is conserved in all Alphabaculoviruses, was modified by SUMO. Mutation of K70 in PKIP led to its translocation from the cytoplasm to the nucleus. Knockout and rescue experiments showed that the rescue of PKIP mutant virus with wild-type PKIP restored BmNPV replication to the normal level, but this was not true for the K70R mutation. Altogether, these results show that SUMOylation of PKIP plays a key role in BmNPV replication