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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.

ABSTRACT: 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.

SUBMITTER: Aouidate A

PROVIDER: S-EPMC6314742 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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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.

Aouidate Adnane A Ghaleb Adib A Ghamali Mounir M Chtita Samir S Ousaa Abdellah A Choukrad M'barek M Sbai Abdelouahid A Bouachrine Mohammed M Lakhlifi Tahar T

In silico pharmacology 20180328 1

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 computat ...[more]

PMID: 30607318

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Project description:This paper presents the results of stationary fluorescence spectroscopy and time-resolved spectroscopy analyses of two 1,3,4-thiadiazole analogues, i.e. 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzene-1,3-diol (C1) and 4-(5-heptyl-1,3,4-thiadiazol-2-yl)benzene-1,3-diol (C7) in an aqueous medium containing different concentrations of hydrogen ions. An interesting dual florescence effect was observed when both compounds were dissolved in aqueous solutions at pH below 7 for C1 and 7.5 for C7. In turn, for C1 and C7 dissolved in water at pH higher than the physiological value (mentioned above), single fluorescence was only noted. Based on previous results of investigations of the selected 1,3,4-thiadiazole compounds, it was noted that the presented effects were associated with both conformational changes in the analysed molecules and charge transfer (CT) effects, which were influenced by the aggregation factor. However, in the case of C1 and C7, the dual fluorescence effects were visible in a higher energetic region (different than that observed in the 1,3,4-thiadiazoles studied previously). Measurements of the fluorescence lifetimes in a medium characterised by different concentrations of hydrogen ions revealed clear lengthening of the excited-state lifetime in a pH range at which dual fluorescence effects can be observed. An important finding of the investigations presented in this article is the fact that the spectroscopic effects observed not only are interesting from the cognitive point of view but also can help in development of an appropriate theoretical model of molecular interactions responsible for the dual fluorescence effects in the analysed 1,3,4-thiadiazoles. Furthermore, the study will clarify a broad range of biological and pharmaceutical applications of these compounds, which are more frequently used in clinical therapies. Graphical Abstract Upper left corner - C7 molecule at high pH, right upper corner - fluorescence emission spectrum for C7 dissolved in H2O at high pH (7-12) - single fluorescence. Bottom left corner - C7 molecule at low pH (1-7), lower right corner - fluorescence emission spectrum for C7 dissolved in water at low pH - two fluorescence emissions. The circles indicate the group related to dissociation of molecules at low and high pH and the additional long circles indicate C1 or a molecule with a shorter acyl chain.

Dataset Information

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.

Publications

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.

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