Cristina Ventura

Modeling Preferential Solvation in Ternary Solvent Systems

The theoretical solvent exchange model of Bosch and Rosés for binary solvents was extended to ternary solvent mixtures. The model was applied to ENT values for the mixture methanol/1-propanol/acetonitrile, in terms of 48 new values in a total of 79, measured at 25 degrees C over the whole range of solvent compositions. It was also applied to the mixture methanollethanol/acetone at the same temperature using 93 E(N)T values obtained from literature. Very good fits between experimental and calculated values, substantiated by external validation methods, were achieved for both sets of data. The use of the developed extended model allowed the interpretation of measured solvatochromic shifts in terms of solute-solvent and solvent-solvent interactions in the local environment of the solutes dye for the two ternary systems and the underlying binary mixtures. It also provided the identification of various complex solvent entities and the quantification of their relative concentrations in the probes cybotactic region, thus leading to new and significant physicochemical insights at a molecular level, regardless of the nonconsideration of the formation of solvent complexes in the bulk. Results clearly showed a different solvent composition in the vicinity of the solute. The further extension of the model to four and five components is also presented.

QSAR Based Design of New Antitubercular Compounds: Improved Isoniazid Derivatives Against Multidrug-Resistant TB

Tuberculosis (TB) is the second cause of death from a single infectious agent, the M. tuberculosis bacillus. Nearly two billion people are infected and about 8.7 million new cases and 1.4 million deaths were reported by the World Health Organization (WHO) in 2013. Despite the availability of effective treatment, the alarming emergence of multidrug resistant (MDR) strains (with 310.000 estimated cases in 2011 among notified patients with pulmonary TB), simultaneously resistant to the two most effective anti-TB drugs, isoniazid (INH) and rifampicin, has urged the need to develop new molecular scaffolds, either structurally original or based on old and active drugs. The aim of this review is to summarize the current status of different QSAR based strategies for the design of novel anti-TB drugs based upon the most active anti-TB agent known, INH. A case study puts in evidence that the judicious application of quantitative structure- activity relationships can be successfully used to rationally design new INH-based derivatives, active against INH-resistant strains harboring mutations in the most frequent resistance related target (katG), and therefore develop candidate-compounds against MDR-TB, thus revisiting the unique effectiveness of INH against TB.

Molecular details of INH-C10 binding to wt KatG and Its S315T mutant.

Isoniazid (INH) is still one of the two most effective antitubercular drugs and is included in all recommended multitherapeutic regimens. Because of the increasing resistance of Mycobacterium tuberculosis to INH, mainly associated with mutations in the katG gene, new INH-based compounds have been proposed to circumvent this problem. In this work, we present a detailed comparative study of the molecular determinants of the interactions between wt KatG or its S315T mutant form and either INH or INH-C10, a new acylated INH derivative. MD simulations were used to explore the conformational space of both proteins, and results indicate that the S315T mutation did not have a significant impact on the average size of the access tunnel in the vicinity of these residues. Our simulations also indicate that the steric hindrance role assigned to Asp137 is transient and that electrostatic changes can be important in understanding the enzyme activity data of mutations in KatG. Additionally, molecular docking studies were used to determine the preferred modes of binding of the two substrates. Upon mutation, the apparently less favored docking solution for reaction became the most abundant, suggesting that S315T mutation favors less optimal binding modes. Moreover, the aliphatic tail in INH-C10 seems to bring the hydrazine group closer to the heme, thus favoring the apparent most reactive binding mode, regardless of the enzyme form. The ITC data is in agreement with our interpretation of the C10 alkyl chain role and helped to rationalize the significantly lower experimental MIC value observed for INH-C10. This compound seems to be able to counterbalance most of the conformational restrictions introduced by the mutation, which are thought to be responsible for the decrease in INH activity in the mutated strain. Therefore, INH-C10 appears to be a very promising lead compound for drug development.