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3D-QSAR models were established by collecting 46 multivariate-substituted 4-oxyquinazoline HDAC6 inhibitors. The relationship of molecular structure and inhibitory activity was studied by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA). The results showed the models established by CoMFA (q2 = 0.590, r2 = 0.965) and CoMSIA (q2 = 0.594, r2 = 0.931) had good prediction ability. At the same time, 3D-QSAR models met the internal verification, external verification and AD test. Ten new compounds were designed based on CoMFA and CoMSIA contour maps and their pharmacokinetic/toxic properties (ADME/T) were evaluated. It was found that most compounds have well safety profile and pharmacokinetic property. Then, we explored the interaction between HDAC6 and compounds by molecular docking. The results showed that the binding mode of the new compounds with HDAC6 was the same as the template compound 46, and the hydrogen bond and hydrophobic bond played a vital role in the binding process. Molecular dynamics simulation results showed that residues Ser531, His574 and Tyr745 played key roles in the binding process. All newly designed compounds had lower energy gap and binding energy than compound 46 according to DFT analysis and free energy analysis. This study provided a theoretical reference for designing compounds of higher activity and a new idea for the development of novel HDAC6 inhibitors. [ABSTRACT FROM AUTHOR]

Highlights: [•] We developed CoMFA, CoMSIA models for a series of 53 3-Pyridine heterocyclic derivatives. [•] Molecular docking method was used to analyses possible interactions between receptors and the compounds. [•] The results of models based ligand alignment and receptor alignment support each other. [•] Ten derivatives as potential candidates of PI3K/mTOR inhibitors with good predicted activities were designed. [Copyright &y& Elsevier]

• We used conventional 3D-QSAR methods to construct models. • Based on the already established models, we designed seven new compounds. • 3、Molecular Dynamics Simulation proved new compound D7 had good selectivity on hCA IX. • 4、The studies may be helpful in the rational drug design of isoform-selective inhibitors. Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R 2>0.75) and predictability (Q 2>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors. [ABSTRACT FROM AUTHOR]

• 52 globomycin analogs were subjected to three-dimensional quantitative conformational relationships research. • Guided by the contour maps from 3D-QSAR models, the regions and strategies for structural optimization were determined. • Combined with molecular docking, molecular dynamics simulations and binding free energy calculations to verify the predicted inhibitory activity of the analogs. • Ten new globomycin analogs with potential were obtained and provided theoretical clues for the design of highly active drugs against E. coli. Lipoprotein signal peptidase II (LspA), a promising therapeutic target for bacterial infections, is essential for the growth of Escherichia coli (E. coli). In this study, 52 globomycin analogs were subjected to three-dimensional quantitative conformational relationships (3D-QSAR) research using comparative molecular field analysis (CoMFA) and the comparative molecular similarity index analysis (CoMSIA) methods. Meanwhile, molecular mechanisms and biological activities were investigated combined with molecular docking and molecular dynamics (MD) simulation. Guided by the contour maps from 3D-QSAR models, we designed 10 novel analogs with potential antimicrobial activity against E. coli. This research could provide theoretical clues for drug design with high activity against E. coli , which was bound to the molecular target LspA. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights: [•] We developed QSAR models for a series of 41 azacycles CCR5 antagonists using CoMFA, CoMSIA and Topomer CoMFA methods. [•] Molecular docking method was used to analyses possible interactions between CCR5 and azacycles derivatives. [•] The results of molecular docking and 3D-QSAR studies supported one another. [•] A set of novel derivatives with predicted activities were designed. [ABSTRACT FROM AUTHOR]

• A three-dimensional QSAR was insight into the structure-activity relationship of 4-aniline-thieno[2,3-d] pyrimidine derivatives (73compounds). • Steric, electrostatic, hydrophobic and hydrogen bond acceptor took into account simultaneously. • To understand the conformational stability and natural dynamics of the interaction in physiological environmental condition, compound 57/D1 and MNK1 were subjected to 100 ns MD simulation. • Theoretical calculations were carried out using density functional theory (DFT). • ADME property analysis also explored for in vivo applicability. MAP kinase interacting serine/threonine kinase 1 (MNK1) can promote the development of tumors through over-activation of MNK and phosphorylation of p-eIF4E, which is an important potential target for cancer therapy. A three-dimensional quantitative structure-activity relationship (3D-QSAR) is applied to investigate the relationship between activities and structures in this paper. Herein, a set of 73 4-aniline-thieno[2,3-d] pyrimidine derivatives were selected, and a 3D-QSAR study was performed by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) model in this paper. The experimental results shown that CoMFA (n = 10; q2 = 0.765; r2 = 0.979), CoMSIA (n = 10; q2 = 0.711; r2 = 0.967) had good stability and predictability. The relationship between the activity and structure of the compound was analyzed by counter maps of the steric, electrostatic and hydrophobic fields. Subsequently, molecular docking was applied to explore key amino acids and docking modes at the active site. Based on the results, 10 new 4-aniline-thieno[2,3-d] pyrimidine derivatives were designed and their activities were predicted. Afterwards, these molecules were submitted to further ADME studies, in which the ADME properties of the 10 designed molecules were found to be within a reasonable range. Molecular Dynamics (MD) simulation analysis confirmed that the residues Leu55, Val63, Lys126, Leu127, Gly130, Ser131, Leu177, Phe192 play a vital role in the active site. In addition, these compounds mainly to bind to MNK1 through lipophilic interactions and hydrogen bonding. These results provided important reference to the discovery and design of new MNK1 inhibitors. [ABSTRACT FROM AUTHOR]

• GSK-3 has been proved as an important therapeutic target in type 2 diabetes mellitus and Alzheimer's disease. • The constructed 3D-QSAR model had good predictive ability. • Based on 3D-QSAR models and contour maps, we designed 10 novel compounds with good potential activity. • We explored the binding feature between GSK-3 and inhibitor by molecular docking and MD simulations. • Residues Ile62, Val70 and Lys85 located in the active site play a key role for GSK-3 complexed with inhibitors. Glycogen Synthase Kinase 3 (GSK-3) is a member of cellular kinase with various functions, such as glucose regulation, cellular differentiation, neuronal function and cell apoptosis. It has been proved as an important therapeutic target in type 2 diabetes mellitus and Alzheimer's disease. To better understand their structure–activity relationships and mechanism of action, an integrated computational study, including three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD), was performed on 79 (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine GSK-3 inhibitors. In this paper, we constructed 3D-QSAR using comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) method. The results showed that the CoMFA model (q 2 = 0.743, r 2 = 0.980) and the CoMSIA model (q 2 = 0.813, r 2 = 0.976) had stable and reliable predictive ability. The electrostatic and H-bond donor fields play important roles in the models. The contour maps of the model visually showed the relationship between the activity of compounds and their three-dimensional structure. Molecular docking was used to identify the key amino acid residues at the active site of GSK-3 and explore its binding mode with ligands. Based on 3D-QSAR models, contour maps and the binding feature between GSK-3 and inhibitor, we designed 10 novel compounds with good potential activity and ADME/T profile. Molecular dynamics simulation results validated that Ile62, Val70 and Lys85 located in the active site play a key role for GSK-3 complexed with inhibitors. These results might provide important information for designing GSK-3 inhibitors with high activity. [ABSTRACT FROM AUTHOR]