Synthesis, Antimicrobial Activities, and Molecular Modeling Studies of Agents for the Sortase A Enzyme.

Sortase A (SrtA) is an attractive target for developing new anti-infective drugs that aim to interfere with essential virulence mechanisms, such as adhesion to host cells and biofilm formation. Herein, twenty hydroxy, nitro, bromo, fluoro, and methoxy substituted chalcone compounds were synthesized, antimicrobial activities and molecular modeling strategies against the SrtA enzyme were investigated. The most active compounds were found to be T2, T4, and T19 against Streptococcus mutans (S. mutans) with MIC values of 1.93, 3.8, 3.94 µg/mL, and docking scores of -6.46, -6.63, -6.73 kcal/mol, respectively. Also, these three active compounds showed better activity than the chlorohexidine (CHX) (MIC value: 4.88 µg/mL, docking score: -6.29 kcal/mol) in both in vitro and in silico. Structural stability and binding free energy analysis of S.mutans SrtA with active compounds were measured by molecular dynamic (MD) simulations throughout 100 nanoseconds (ns) time. It was observed that the stability of the critical interactions between these compounds and the target enzyme was preserved. To prove further, in vivo biological evaluation studies could be conducted for the most promising precursor compounds T2, T4, and T19, and it might open new avenues to the discovery of more potent SrtA inhibitors.

Evaluation of the effects of chlorhexidine and several flavonoids as antiviral purposes on SARS-CoV-2 main protease: molecular docking, molecular dynamics simulation studies.

The recent outbreak of COVID-19 caused by a new human coronavirus called SARS-CoV-2, is continually causing worldwide human infections and deaths.The main protease (3CLpro), which plays a critical role in the life cycle of the virus, makes it an attractive target for the development of antiviral agents effective against coronaviruses (CoVs).Currently, there is no specific viral protein targeted therapeutics.Therefore, there is a need to investigate an alternative therapy which will prevent the spread of the infection, by focusing on the transmission of the virus.Chlorhexidine (CHX) and flavonoids agents have shown that they have a viral inactivation effect against enveloped viruses, and thus facilitate the struggle against oral transmission.Especially, some flavonoids have very strong antiviral activity in SARS-CoV and MERS-CoV main protease.This study was conducted to evaluate the CHX and flavonoids compounds potential antiviral effects on SARS-CoV-2 main protease through virtual screening for the COVID-19 treatment by molecular docking method.According to the results of this study, CHX, Kaempferol-3-rutinoside, Rutin, Quercetin 3-beta-D-glucoside and Isobavachalcone exhibited the best binding affinity against this enzyme, and also these compounds showed significant inhibitory effects compared to the SARS-CoV-2 main protease crystal structure inhibitor (N3).Especially, these compounds mainly interact with His41, Cys145, His163, Met165, Glu166 and Thr190 in SARS-CoV-2 main protease binding site. Further, MD simulation analysis also confirmed that stability of these interactions between the enzyme and these five compounds.The current study provides to guide clinical trials for broad-spectrum CHX and bioactive flavonoids to reduce the viral load of the infection and possibly disease progression.Communicated by Ramaswamy H. Sarma.

Investigation of the antimicrobial activities of various antimicrobial agents on Streptococcus Mutans Sortase A through computer-aided drug design (CADD) approaches.

BACKGROUND AND OBJECTIVE: Tooth decay is a common chronic disease that causes pain, tooth loss, malnutrition, anxiety and significantly affects half of the world's population. Streptococcus mutans (S.mutans), is considered the main pathogen causing tooth decay. Sortase A (SrtA), one of the surface proteins of S. mutans, is a potential target in the development of antimicrobial and caries prevention agents for preventing infections associated with biofilm formation. Recently, various SrtA inhibitors, including small molecules and natural product, especially, trans-chalcone, chlorhexidine (CHX) and flavonoid compounds, which exhibit effective inhibition against SrtA, have been identified. However, due to the limited number of inhibitors, multi-drug resistance and side-effects the discovery of new inhibitors for SrtA is essential. METHODS: In this case, various compounds aimed at the target enzyme underwent high-throughput screening with small molecule libraries. For this screening of a total of 178 compounds, 163 were found to be pharmacokinetically suitable by performing an absorption, distribution, metabolism, and excretion (ADME) analysis. Molecular docking was then applied to investigate the interaction mechanism among these suitable compounds and the target enzyme structure at the molecular level. RESULTS: According to the results of the study, six compounds (CHEMBL243796 (kurarinone), CHEMBL2180472, CHEMBL3335591, CHEMBL373249, CHEMBL1395334, CHEMBL253467 (Isobavachalcone)) exhibited lower docking scores (-7.18, -6.59, -6.53, -6.47, -6.43, and -6.39 kcal/mol, respectively) against S. mutans SrtA than the positive control CHX (-6.29 kcal/mol). Finally, the 100 ns molecular dynamic simulations and binding free energy calculations were performed for the structure stability analysis of the enzyme with CHEMBL243796 (kurarinone), which showed the lowest docking score. As a result of these studies, the stability of the critical interactions between kurarinone and the target enzyme was preserved during the simulation time. CONCLUSIONS: These results indicate that flavonoid and chalcone scaffold compounds are clinically more reliable and potent than CHX as novel inhibitory agents for inhibiting oral biofilm formation. These finding can provide important contribution to the future clinical trials in the development of therapeutically useful inhibitors of SrtA by virtually screening several chemical compounds more rapidly to select suitable compounds for the prevention and treatment of dental caries.