A Computational Approach Applied to the Study of Potential Allosteric Inhibitors Protease NS2B/NS3 from Dengue Virus.

Dengue virus (DENV) is a danger to more than 400 million people in the world, and there is no specific treatment. Thus, there is an urgent need to develop an effective method to combat this pathology. NS2B/NS3 protease is an important biological target due it being necessary for viral replication and the fact that it promotes the spread of the infection. Thus, this study aimed to design DENV NS2B/NS3pro allosteric inhibitors from a matrix compound. The search was conducted using the Swiss Similarity tool. The compounds were subjected to molecular docking calculations, molecular dynamics simulations (MD) and free energy calculations. The molecular docking results showed that two compounds, ZINC000001680989 and ZINC000001679427, were promising and performed important hydrogen interactions with the Asn152, Leu149 and Ala164 residues, showing the same interactions obtained in the literature. In the MD, the results indicated that five residues, Lys74, Leu76, Asn152, Leu149 and Ala166, contribute to the stability of the ligand at the allosteric site for all of the simulated systems. Hydrophobic, electrostatic and van der Waals interactions had significant effects on binding affinity. Physicochemical properties, lipophilicity, water solubility, pharmacokinetics, druglikeness and medicinal chemistry were evaluated for four compounds that were more promising, showed negative indices for the potential penetration of the Blood Brain Barrier and expressed high human intestinal absorption, indicating a low risk of central nervous system depression or drowsiness as the the side effects. The compound ZINC000006694490 exhibited an alert with a plausible level of toxicity for the purine base chemical moiety, indicating hepatotoxicity and chromosome damage in vivo in mouse, rat and human organisms. All of the compounds selected in this study showed a synthetic accessibility (SA) score lower than 4, suggesting the ease of new syntheses. The results corroborate with other studies in the literature, and the computational approach used here can contribute to the discovery of new and potent anti-dengue agents.

Biological maturation influences selection process in youth elite soccer players.

This study examined the influence of birth date, salivary testosterone [sT] concentration, sexual maturity status, and general strength on the selection process of an elite Brazilian soccer club during a 12-month period, which was a 2nd phase of a 24-month selection process. The stature, body mass, sT, sexual maturity status [Tanner scale], and hand grip strength were assessed for 143 players during 2 weeks. From these 143 players, 100 players were dismissed [DIS] and 43 players were selected to integrate the club's under-14 squad. Following 1-year training period, the under-14 team was assembled with 9 players designated as starters [STA], and then, comparisons were conducted taking into account a group of non-starters (selected; SEL = 34 players) and STA (n = 09). The DIS, SEL, STA players, and reference population, were compared for birth distribution. A greater proportion of players was born in the first trimester in the STA [75.0%], SEL [57.1%] and DIS [50.0%] groups compared to the reference population [25.8%]. One-way ANOVA showed a higher sT for STA group [516.0 ± 129.9 pmol·L-1], compared to SEL [415.5 ± 117.9 pmol·L-1] and DIS groups [390.9 ± 84.9 pmol·L-1; p = 0.003), and Kruskall-Wallis test showed a higher gonadal development for STA compared to DIS [p = 0.001]. The current findings suggest a strong influence of birth date and biological maturation on young soccer players selection process. Soccer coaches should consider these influences when making decisions about player selection of elite youth players.