ABSTRACT
In the search for inhibitors of COVID-19, we have targeted the interaction between the human angiotensin-converting enzyme 2 (ACE2) receptor and the spike receptor binding domain (S1-RBD) of SARS-CoV-2. Virtual screening of a library of natural compounds identified Kobophenol A as a potential inhibitor. Kobophenol A was then found to block the interaction between the ACE2 receptor and S1-RBD in vitro with an IC50 of 1.81 ± 0.04 µM and inhibit SARS-CoV-2 viral infection in cells with an EC50 of 71.6 µM. Blind docking calculations identified two potential binding sites, and molecular dynamics simulations predicted binding free energies of -19.0 ± 4.3 and -24.9 ± 6.9 kcal/mol for Kobophenol A to the spike/ACE2 interface and the ACE2 hydrophobic pocket, respectively. In summary, Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19.
Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19 Drug Treatment , Drug Design , Receptors, Coronavirus/metabolism , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Stilbenes/pharmacology , Animals , Chlorocebus aethiops , Computer Simulation , Humans , Hydrophobic and Hydrophilic Interactions , Molecular Docking Simulation , Protein Binding , SARS-CoV-2/metabolism , Vero CellsABSTRACT
Objective To investigate the possible associations of two polymorphisms (5-HTTLPR and STin2VNTR)of the serotonin transporter gene with alcohol use disorders (AUD).Methods 281 AUD cases (AUDIT score≥ 10) and 277 healthy controls (AUDIT score ≤5) were recruited in this study.All participants were genotyped using the PCR technique.Results The frequency of the L-allele of the 5-HTTLPR was 39.01％,and the 10-allele of STin2VNTR was 8.42％ in this population,the allele frequencies of both polymorphisms were consistent with Asian normal populations.No significant association was observed between 5-HTTLPR and AUD,but the genotypic and allele frequencies of the STin2VNTR were significant different between two groups even after Bonferroni adjustment,the 12 repeat allele of the STin2VNTR was significantly associated with the risk effect for AUD.Haplotype analysis for those two polymorphisms revealed no association between 4 haplotype combinations and AUD.Conclusion There is no relationship between 5-HTTLPR and AUD.The STin2VNTR polymorphism of 5-HTT may play a role in the pathogenesis of AUD.
