Leishmanicidal activity and 4D quantitative structure-activity relationship and molecular docking studies of vanillin-containing 1,2,3-triazole derivatives.

Aim: The assessment of the antileishmanial potential of 22 vanillin-containing 1,2,3-triazole derivatives against Leishmania braziliensis is reported. Materials & methods: Initial screening was performed against the parasite promastigote form. The most active compound, 4b, targeted parasites within amastigotes (IC50 = 4.2 ± 1.0 µmol l-1), presenting low cytotoxicity and a selective index value of 39. 4D quantitative structure-activity relationship and molecular docking studies provided insights into structure-activity and biological effects. Conclusion: A vanillin derivative with significant antileishmanial activity was identified. Enhanced activity was linked to increased electrostatic and Van der Waals interactions near the benzyl ring of the derivatives. Molecular docking indicated the inhibition of the Leishmania amazonensis sterol 14α-demethylase, using Leishmania infantum sterol 14α-demethylase as a model, without affecting the human isoform. Inhibition was active site competition with lanosterol.

Traditional herbal compounds as candidates to inhibit the SARS-CoV-2 main protease: an in silico study.

COVID-19, a disease caused by the SARS-CoV-2 virus, is responsible for a pandemic since March 2020 and it has no cure. Therefore, herein, different theoretical methods were used to obtain potential candidates from herbal compounds to inhibit the SARS-CoV-2 main protease (Mpro). Initially, the 16 best-scored compounds were selected from a library containing 4066 ligands using virtual screening by molecular docking. Among them, six molecules (physalin B 5,6-epoxide (PHY), methyl amentoflavone (MAM), withaphysalin C (WPC), daphnoline or trilobamine (TRI), cepharanoline (CEP) and tetrandrine (TET)) were selected based on Lipinski's rule and ADMET analysis as criteria. These compounds complexed with the Mpro were submitted to triplicate 100 ns molecular dynamics simulations. RMSD, RMSF, and radius of gyration results show that the overall protein structure is preserved along the simulation time. The average ΔGbinding values, calculated by the MM/PBSA method, were -41.7, -55.8, -45.2, -38.7, -49.3, and -57.9 kcal/mol for the PHY-Mpro, MAM-Mpro, WPC-Mpro, CEP-Mpro, TRI-Mpro, and TET-Mpro complexes, respectively. Pairwise decomposition analyses revealed that the binding pocket is formed by His41-Val42, Met165-Glu166-Leu167, Asp187, and Gln189. The PLS regression model generated by QSPR analysis indicated that non-polar and polar groups with the presence of hydrogen bond acceptors play an important role in the herbal compounds-Mpro interactions. Overall, we found six potential candidates to inhibit the SARS-CoV-2 Mpro and highlighted key residues from the binding pocket that can be used for future drug design. Communicated by Ramaswamy H. Sarma.

Single-walled silicon nanotube as an exceptional candidate to eliminate SARS-CoV-2: a theoretical study.

In this work, computational chemistry methods were used to study a silicon nanotube (Si192H16) as possible virucidal activity against SARS-CoV-2. This virus is responsible for the COVID-19 disease. DFT calculations showed that the structural parameters of the Si192H16 nanotube are in agreement with the theoretical/experimental parameters reported in the literature. The low energy gap value (0.29 eV) shows that this nanotube is a semiconductor and exhibits high reactivity. For nanomaterials to be used as virucides, they need to have high reactivity and high inhibition constant values. Therefore, the adsorption of 3O2 and H2O on the surface of Si192H16 (Si192H16@O2-H2O) was performed. In this process, the formation and activation energies were -51.63 and 16.62 kcal/mol, respectively. Molecular docking calculations showed that the Si192H16 and Si192H16@O2H-OH nanotubes bind favorably on the receptor-binding domain of the SARS-CoV-2 spike protein with binding energy of -11.83 (Ki = 2.13 nM) and -11.13 (Ki = 6.99 nM) kcal/mol, respectively. Overall, the results obtained herein indicate that the Si192H16 nanotube is a potential candidate to be used against COVID-19 from reactivity process and/or steric impediment in the S-protein.Communicated by Ramaswamy H. Sarma.

Insights into ß-amyloid transition prevention by cucurbit[7]uril from molecular modeling.

In this study, comparable molecular dynamic (MD) simulations of 1.2 microseconds were performed to clarify the prevention of the ß-amyloid peptide (Aß1-42) aggregation by cucurbit[7]uril (CB[7]). The accumulation of this peptide in the brain is one of the most harmful in Alzheimer's disease. The inhibition mechanism of Aß1-42 aggregation by different molecules is attributed to preventing of Aß1-42 conformational transition from α-helix to the ß-sheet structure. However, our structural analysis shows that the pure water and aqueous solution of the CB[7] denature the native Aß1-42 α-helix structure forming different compactness and unfolded conformations, not in ß-sheet form. On the other hand, in the three CB[7]@Aß1-42 complexes, it was observed the encapsulation of N-terminal (Asp1), Lys16, and Val36 by CB[7] along the MD trajectory, and not with aromatic residues as suggested by the literature. Only in one CB[7]@Aß1-42 complex was observed stable Asp23-Lys28 salt bridge with an average distance of 0.36 nm. All CB[7]@Aß1-42 complexes are very stable with binding free energy lowest than ∼-50 kcal/mol between the CB[7] and Aß1-42 monomer from MM/PBSA calculation. Therefore, herein we show that the mechanism of the prevention of elongation protofibril by CB[7] is due to the disruption of the Asp23-Lys28 salt bridge and steric effects of CB[7]@Aß1-42 complex with the fibril lattice, and not due to the transition from α-helix to ß-sheet following the dock-lock mechanism.Communicated by Ramaswamy H. Sarma.

Repurposing approved drugs as inhibitors of SARS-CoV-2 S-protein from molecular modeling and virtual screening.

Herein, molecular modeling techniques were used with the main goal to obtain candidates from a drug database as potential targets to be used against SARS-CoV-2. This novel coronavirus, responsible by the COVID-19 outbreak since the end of 2019, became a challenge since there is not vaccine for this disease. The first step in this investigation was to solvate the isolated S-protein in water for molecular dynamics (MD) simulation, being observed a transition from "up" to "down" conformation of receptor-binding domain (RBD) of the S-protein with angle of 54.3 and 43.0 degrees, respectively. The RBD region was more exposed to the solvent and to the possible drugs due to its enhanced surface area. From the equilibrated MD structure, virtual screening by docking calculations were performed using a library contained 9091 FDA approved drugs. Among them, 24 best-scored ligands (14 traditional herbal isolate and 10 approved drugs) with the binding energy below -8.1 kcal/mol were selected as potential candidates to inhibit the SARS-CoV-2 S-protein, preventing the human cell infection and their replication. For instance, the ivermectin drug (present in our list of promise candidates) was recently used successful to control viral replication in vitro. MD simulations were performed for the three best ligands@S-protein complexes and the binding energies were calculated using the MM/PBSA approach. Overall, it is highlighted an important strategy, some key residues, and chemical groups which may be considered on clinical trials for COVID-19 outbreak. [Formula: see text]Communicated by Ramaswamy H. Sarma.

Solvation of sodium octanoate micelles in concentrated urea solution studied by means of molecular dynamics simulations.

The effects of urea on self-assembling remains a challenging topic on surface chemistry, and computational modeling may have a role on the unraveling of the molecular mechanisms underlying these effects. Bearing that in mind, we performed a set of molecular dynamics simulations to assess the effects of urea on the self-assembling properties of sodium octanoate, an anionic surfactant, as compared to the aggregation of the same surfactant in pure water as the solvent. The concentration of free monomers increased 3-fold in the presence of urea, in agreement with the accepted view that urea should increase monomer solubility. Regarding the size distribution of micellar aggregates, the urea solution favored smaller micelles and a narrower distribution. Preferential solvation by either water or urea changed along the surfactant molecules, from urea-rich shells around apolar atoms at the end of the hydrophobic tails to nearly no urea at the polar headgroups. This solvation profile is consistent with two different hypotheses from the literature: on one hand, urea molecules interact directly with apolar atoms from the hydrophobic tails, acting as a surfactant, and on the other hand the presence of urea molecules increases the hydration of polar sites. Another important observation regards the solvent structure, which exhibits a complex composition profile around both water and urea molecules. Although the solvent structure was appreciably different in each case, the free energy calculations for the dissociation of a pair of octanoate molecules pointed to a purely enthalpic free energy loss in urea solution, a finding that does not lend support to the third hypothesis that is often claimed as accounting for the urea effects, namely, that urea disrupts water structure and that this structural change decreases the hydrophobic effect due to an entropy change. The presence of urea had no significant effect on the molecular structure of the surfactant molecules, although it caused chain dynamics to become slower. The overall picture arising from the molecular-scale data extracted from our computational models is somewhat different from the traditional views about the structural and dynamical features of self-assembled surfactant systems, pointing out the need for more studies on other self-organized systems using a realistic model system as a way to achieve a more detailed picture.