Screening and Biological Evaluation of Soluble Epoxide Hydrolase Inhibitors: Assessing the Role of Hydrophobicity in the Pharmacophore-Guided Search of Novel Hits.

The human soluble epoxide hydrolase (sEH) is a bifunctional enzyme that modulates the levels of regulatory epoxy lipids. The hydrolase activity is carried out by a catalytic triad located at the center of a wide L-shaped binding site, which contains two hydrophobic subpockets at both sides. On the basis of these structural features, it can be assumed that desolvation is a major factor in determining the maximal achievable affinity that can be attained for this pocket. Accordingly, hydrophobic descriptors may be better suited to the search of novel hits targeting this enzyme. This study examines the suitability of quantum mechanically derived hydrophobic descriptors in the discovery of novel sEH inhibitors. To this end, three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophores were generated by combining electrostatic and steric or alternatively hydrophobic and hydrogen-bond parameters in conjunction with a tailored list of 76 known sEH inhibitors. The pharmacophore models were then validated by using two external sets chosen (i) to rank the potency of four distinct series of compounds and (ii) to discriminate actives from decoys, using in both cases datasets taken from the literature. Finally, a prospective study was performed including a virtual screening of two chemical libraries to identify new potential hits, which were subsequently experimentally tested for their inhibitory activity on human, rat, and mouse sEH. The use of hydrophobic-based descriptors led to the identification of six compounds as inhibitors of the human enzyme with IC50 < 20 nM, including two with IC50 values of 0.4 and 0.7 nM. The results support the use of hydrophobic descriptors as a valuable tool in the search of novel scaffolds that encode a proper hydrophilic/hydrophobic distribution complementary to the target's binding site.

Assessing the Performance of Mixed Strategies To Combine Lipophilic Molecular Similarity and Docking in Virtual Screening.

The accuracy of structure-based (SB) virtual screening (VS) is heavily affected by the scoring function used to rank a library of screened compounds. Even in cases where the docked pose agrees with the experimental binding mode of the ligand, the limitations of current scoring functions may lead to sensible inaccuracies in the ability to discriminate between actives and inactives. In this context, the combination of SB and ligand-based (LB) molecular similarity may be a promising strategy to increase the hit rates in VS. This study explores different strategies that aim to exploit the synergy between LB and SB methods in order to mitigate the limitations of these techniques, and to enhance the performance of VS studies by means of a balanced combination between docking scores and three-dimensional (3D) similarity. Particularly, attention is focused to the use of measurements of molecular similarity with PharmScreen, which exploits the 3D distribution of atomic lipophilicity determined from quantum mechanical-based continuum solvation calculations performed with the MST model, in conjunction with three docking programs: Glide, rDock, and GOLD. Different strategies have been explored to combine the information provided by docking and similarity measurements for re-ranking the screened ligands. For a benchmarking of 44 datasets, including 41 targets, the hybrid methods increase the identification of active compounds, according to the early (ROCe%) and total (AUC) enrichment metrics of VS, compared to pure LB and SB methods. Finally, the hybrid approaches are also more effective in enhancing the chemical diversity of active compounds. The datasets employed in this work are available in https://github.com/Pharmacelera/Molecular-Similarity-and-Docking.

Development and Validation of Molecular Overlays Derived from Three-Dimensional Hydrophobic Similarity with PharmScreen.

Molecular alignment is a standard procedure for three-dimensional (3D) similarity measurements and pharmacophore elucidation. This process is influenced by several factors, such as the physicochemical descriptors utilized to account for the molecular determinants of biological activity and the reference templates. Relying on the hypothesis that the maximal achievable binding affinity for a drug-like molecule is largely due to desolvation, we explore a novel strategy for 3D molecular overlays that exploits the partitioning of molecular hydrophobicity into atomic contributions in conjunction with information about the distribution of hydrogen-bond (HB) donor/acceptor groups. A brief description of the method, as implemented in the software package PharmScreen, including the derivation of the fractional hydrophobic contributions within the quantum mechanical version of the Miertus-Scrocco-Tomasi (MST) continuum model, and the procedure utilized for the optimal superposition between molecules, is presented. The computational procedure is calibrated by using a data set of 402 molecules pertaining to 14 distinct targets taken from the literature and validated against the AstraZeneca test, which comprises 121 experimentally derived sets of molecular overlays. The results point out the suitability of the MST-based hydrophobic parameters for generating molecular overlays, as correct predictions were obtained for 94%, 79%, and 54% of the molecules classified into easy, moderate, and hard sets, respectively. Moreover, the results point out that this accuracy is attained at a much lower degree of identity between the templates used by hydrophobic/HB fields and electrostatic/steric ones. These findings support the usefulness of the hydrophobic/HB descriptors to generate complementary overlays that may be valuable to rationalize structure-activity relationships and for virtual screening campaigns.

Multiple stressor effects on biological quality elements in the Ebro River: Present diagnosis and predicted responses.

Multiple abiotic stressors affect the ecological status of water bodies. The status of waterbodies in the Ebro catchment (NE Spain) is evaluated using the biological quality elements (BQEs) of diatoms, invertebrates and macrophytes. The multi-stressor influence on the three BQEs was evaluated using the monitoring dataset available from the catchment water authority. Nutrient concentrations, especially total phosphorus (TP), affected most of the analyzed BQEs, while changes in mean discharge, water temperature, or river morphology did not show significant influences. Linear statistical models were used to evaluate the change of water bodies' ecological status under different combinations of future socioeconomic and climate scenarios. Changes in land use, rainfall, water temperature, mean discharge, TP and nitrate concentrations were modeled according to the future scenarios. These revealed an evolution of the abiotic stressors that could lead to a general decrease in the ecosystem quality of water bodies within the Ebro catchment. This deterioration was especially evidenced on the diatoms and invertebrate biological indices, mainly because of the foreseen increase in TP concentrations. Water bodies located in the headwaters were seen as the most sensitive to future changes.