3D QSAR studies, molecular docking and ADMET evaluation, using thiazolidine derivatives as template to obtain new inhibitors of PIM1 kinase.

Proviral Integration site for Moloney murine leukemia virus-1 (PIM1) belongs to the serine/threonine kinase family of Ca2+-calmodulin-dependent protein kinase (CAMK) group, which is involved in cell survival and proliferation as well as a number of other signal transduction pathways. Thus, PIM1 is regarded as a promising target for treatment of cancers. In the present paper, a three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking were performed to investigate the binding between PIM1 and thiazolidine inhibitors in order to design potent inhibitors. The comparative molecular similarity indices analysis (CoMSIA) was developed using twenty-six molecules having pIC50 ranging from 8.854 to 6.011 (IC50 in nM). The best CoMSIA model gave significant statistical quality. The determination coefficient (R2) and Leave-One-Out cross-validation coefficient (Q2) are 0.85 and 0.58, respectively. Furthermore, the predictive ability of this model was evaluated by external validation((n = 11, R2test = 0.72, and MAE = 0.170 log units). The graphical contour maps could provide structural features to improve inhibitory activity. Furthermore, a good consistency between contour maps and molecular docking strongly demonstrates that the molecular modeling is reliable. Based on these satisfactory results, we designed several new potent PIM1 inhibitors and their inhibitory activities were predicted by the molecular models. Additionally, those newly designed inhibitors, showed promising results in the preliminary in silico ADMET evaluations, compared to the best inhibitor from the studied dataset. The results expand our understanding of thiazolidines as inhibitors of PIM1 and could be of great help in lead optimization for early drug discovery of highly potent inhibitors.

Computer aided drug design based on 3D-QSAR and molecular docking studies of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amine derivatives as PIM2 inhibitors: a proposal to chemists.

PIM2 kinase plays a crucial role in the cell cycle events including survival, proliferation, and differentiation in normal and neoplastic neuronal cells. Thus, it is regarded as an essential target for cancer pharmaceutical. Design of novel 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amine derivatives with enhanced PIM2 inhibitory activity. A series of twenty-five PIM2 inhibitors reported in the literature containing 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines scaffold was studied by using two computational techniques, namely, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indexes analysis (CoMSIA) studies were developed using nineteen molecules having pIC50 ranging from 8.222 to 4.157. The best generated CoMFA and CoMSIA models exhibit conventional determination coefficients R2 of 0.91 and 0.90 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.68 and 0.62, respectively. Moreover, the predictive ability of those models was evaluated by the external validation using a test set of six compounds with predicted determination coefficients Rtest 2 of 0.96 and 0.96, respectively. Besides, y-randomization test was also performed to validate our 3D-QSAR models. The most and the least active compounds were docked into the active site of the protein (PDB ID: 4 × 7q) to confirm those obtained results from 3D-QSAR models and elucidate the binding mode between this kind of compounds and the PIM2 enzyme. These satisfactory results are not offered help only to understand the binding mode of 5-(1H-indol-5-yl)-1,3,4-thiadiazol series compounds into this kind of targets, but provide information to design new potent PIM2 inhibitors.

Total Fluorescence Fingerprinting of Pesticides: A Reliable Approach for Continuous Monitoring of Soils and Waters.

The present work relates to the creation/extension of a database of Total Excitation-Emission and Total Synchronous Fluorescence Matrices (TEEMs and TSFMs) along with optimal Synchronous Fluorescence Spectra (SFS) to fingerprint pesticides widely used in Morocco. This spectrometric multi-component fingerprinting may permit the direct detection of pesticides persisting in soil or water. The objective of the current investigation is to detect four pesticide remains in agricultural soils by applying the spectrometric fingerprinting results. They are the commercial: i) insecticide Axlera 5G (carbamate), ii) fungicide Orsalis 5% SC (triazole), iii) insecticide Force 0,5 G (pyrethrinoid) and iv) insecticide Proclaim 05 SG (non-assigned). The agricultural plantations monitored are located in the great agricultural Doukkala region at the western Atlantic side of Morocco, where these chemicals are in large sale and use.