Econometric model of iron ore through principal component analysis and multiple linear regression.

Price of iron ore is affected by instabilities of microeconomic balance between supply and demand. Periods of equilibrium adjustment result in huge swings, growth or global recession. They also impact the viability of mineral enterprises and generate consequences to important global economic scenarios. This research aims to evaluate the market variables capable of influencing the price of iron ore through multivariate statistical techniques. Principal component analysis and multiple linear regression, booth multivariate statistical techniques were used. The studied variables were rate export of iron ore and concentrates from Brazil, steel production from China, steel production from Japan, production from Europe, steel production from the United States, steel production from India, steel price, coal price, China's Construction Gross Domestic Production, United States construction index, oil price and global oil production. First three components explained 89.12% of the variability of the data matrix. Multiple linear regression highlighted the significance of five variables. They are export iron ore from Brazil, steel production from China, price of coal, steel production from India and price of steel.

Identification of novel F508del-CFTR traffic correctors among triazole derivatives.

The most prevalent cystic fibrosis (CF)-causing mutation - F508del - impairs the folding of CFTR protein, resulting in its defective trafficking and premature degradation. Small molecules termed correctors may rescue F508del-CFTR and therefore constitute promising pharmacotherapies acting on the fundamental cause of the disease. Here, we screened a collection of triazole compounds to identify novel F508del-CFTR correctors. The functional primary screen identified four hit compounds (LSO-18, LSO-24, LSO-28, and LSO-39), which were further validated and demonstrated to rescue F508del-CFTR processing, plasma membrane trafficking, and function. To interrogate their mechanism of action (MoA), we examined their additivity to the clinically approved drugs VX-661 and VX-445, low temperature, and genetic revertants of F508del-CFTR. Rescue of F508del-CFTR processing and function by LSO-18, LSO-24, and LSO-28, but not by LSO-39, was additive to VX-661, whereas LSO-28 and LSO-39, but not LSO-18 nor LSO-24, were additive to VX-445. All compounds under investigation demonstrated additive rescue of F508del-CFTR processing and function to low temperature as well as to rescue by genetic revertants G550E and 4RK. Nevertheless, none of these compounds was able to rescue processing nor function of DD/AA-CFTR, and LSO-39 (similarly to VX-661) exhibited no additivity to genetic revertant R1070W. From these findings, we suggest that LSO-39 (like VX-661) has a putative binding site at the NBD1:ICL4 interface, LSO-18 and LSO-24 seem to share the MoA with VX-445, and LSO-28 appears to act by a different MoA. Altogether, these findings represent an encouraging starting point to further exploit this chemical series for the development of novel CFTR correctors.

Searching for potential drugs against SARS-CoV-2 through virtual screening on several molecular targets.

The acute respiratory syndrome caused by the SARS-CoV-2, known as COVID-19, has been ruthlessly tormenting the world population for more than six months. However, so far no effective drug or vaccine against this plague have emerged yet, despite the huge effort in course by researchers and pharmaceutical companies worldwide. Willing to contribute with this fight to defeat COVID-19, we performed a virtual screening study on a library containing Food and Drug Administration (FDA) approved drugs, in a search for molecules capable of hitting three main molecular targets of SARS-CoV-2 currently available in the Protein Data Bank (PDB). Our results were refined with further molecular dynamics (MD) simulations and MM-PBSA calculations and pointed to 7 multi-target hits which we propose here for experimental evaluation and repurposing as potential drugs against COVID-19. Additional rounds of docking, MD simulations and MM-PBSA calculations with remdesivir suggested that this compound can also work as a multi-target drug against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

In Silico Studies of Potential Selective Inhibitors of Thymidylate Kinase from Variola virus.

Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.

Lipophilicity of Coarse-Grained Cholesterol Models.

The lipophilicity of cholesterol was investigated by using coarse-grained molecular dynamics and umbrella sampling. The previous coarse-grained cholesterol models in the literature are more hydrophobic than our model. The Gibbs free energy of transferring cholesterol from the octanol phase to water phase (ΔGo/w) was 11.88 ± 0.08 kcal mol-1, and the octanol-water partitioning coefficient (logP) was estimated to be 8.72 ± 0.06. The latter is in agreement with the logP values found by bioinformatics, which are standard methods to predict the lipophilicity, giving excellent octanol/water partitioning coefficients compared with experimental ones for different molecules. We also performed the first experimentally direct measurement of this important property for cholesterol. The experimental octanol/water partitioning coefficient of cholesterol was measured to be 8.86 ± 0.79, which is in excellent agreement with our calculated logP value from our parametrized coarse-grained cholesterol model. This shows the significance of systematic optimization of the lipophilicity for developing coarse-grain models of important biomolecules with complicated molecular structures and hydrophobic character like cholesterol.

Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox.

Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK.