ABSTRACT
The development of small and medium-sized businesses should become a priority in the implementation of economic policy. The introduction of a number of anti-epidemic measures aimed at combating the COVID-19 pandemic has become an unprecedented challenge primarily for small and medium-sized businesses not only in Russia, but also in the world as a whole. Therefore, it is important to generalize practical experience, as well as to compare the indicators of development of small and medium-sized businesses in Russia and other European countries in order to determine strategies that will set the vector of development of the country's competitiveness and ensure accelerated economic growth.
ABSTRACT
Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme in the biosynthesis of pyrimidine, which catalyzes the oxidation of dihydroorotate to orotate. Uridine monophosphate is biosynthesized by orotate. DHODH inhibitors have been shown to have antiviral activity against cytomegalovirus, Ebola, influenza, Epstein-Barr virus, and picornavirus. The anti-SARS-CoV-2 activity of DHODH inhibitors has also been investigated. DHODH inhibitors, including leflunomide and its metabolite teriflunomide, have been found to have anti-SARSCoV-2 activity. In relation to the importance of this enzyme (i.e., DHODH) in drug design, the present study aimed to develop statistically robust and interpretable 2D and 3D-quantitative structure-activity relationship (QSAR) models based on a dataset of 92 molecules of biologically active 2-aryl-4-quinoline carboxylic acid analogs, reported as DHODH inhibitors. The correlation coefficient (R2) values of the training set of the partial least squares (PLS) and all five Kernel-based PLS models for the respective fingerprints were found to be 0.7091, 0.8336 (linear), 0.7586 (radial), 0.8606 (dendritic), 0.6832 (desc), and 0.7670 (Molprint 2D), respectively (R2 ≈ 0.9). However, the external validation coefficient (Q2) values of the test set were found to be 0.7009, 0.7503 (linear), 0.7737 (radial), 0.8250 (dendritic), 0.6756 (desc), and 0.7533 (Molprint 2D), respectively (Q2 > 0.6). The developed 4-point pharmacophore model (ARRR_1), with one hydrogen bond acceptor and three aromatic rings, was found to be crucial in preserving the activity of 2-aryl-4-quinoline carboxylic acid analogs as DHODH inhibitors. Furthermore, the molecular docking of DHODH inhibitors against SARS-CoV-2 target proteins revealed the significant role of DHODH inhibitors. © 2023, Physical Chemistry Research. All Rights Reserved.
ABSTRACT
The recent release of SARS-CoV-2 genomic data from several countries has provided clues into the potential antigenic drift of the coronavirus population. In particular, the genomic instability observed in the spike protein necessitates immediate action and further exploration in the context of viral-host interactions. By temporally tracking 527,988 SARS-CoV-2 genomes, we identified invariant and hypervariable regions within the spike protein. We evaluated combination of mutations from SARS-CoV-2 lineages and found that maximum number of lineage-defining mutations were present in the N-terminal domain (NTD). Based on mutant 3D-structural models of known Variants of Concern (VOCs), we found that structural properties such as accessibility, secondary structural type, and intra-protein interactions at local mutation sites are greatly altered. Further, we observed significant differences between intra-protein networks of wild-type and Delta mutant, with the latter showing dense intra-protein contacts. Extensive molecular dynamics simulations of D614G mutant spike structure with hACE2 further revealed dynamic features with 47.7% of mutations mapping on flexible regions of spike protein. Thus, we propose that significant changes within spike protein structure have occurred that may impact SARS-CoV-2 pathogenesis, and repositioning of vaccine candidates is required to contain the spread of COVID-19 pathogen.