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Myocarditis is classified as an inflammatory disease of the heart muscle and is a leading cause of sudden death. The Keap1-Nrf2-ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1-Nrf2 protein–protein interaction (PPI) is considered as a potential drug target against myocarditis to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes. To gain insights into the relationship between the activity and structure of the compounds and design superior active novel inhibitors, 3D-QSAR, molecular docking and molecular dynamics (MD) simulation were combined to investigate the interaction between Keap1–Nrf2 PPI inhibitors and Keap1. The comparative molecular field analysis (CoMFA) model (q2 = 0.907, n = 7, R2 = 0.997) and the comparative molecular similarity index analysis (CoMSIA) model (q2 = 0.900, n = 7, and R2 = 0.993) showed that the 3D-QSAR models built were credible and predictable. Based on these models, 10 new compounds were discovered and their bioactivity was validated using molecular docking and MD simulation. Furthermore, the plausible ADME/T characteristics of new compounds were evaluated and the key residues (Arg415, Tyr334, Ser602, Ser363, Arg380, etc.) in the active site were also identified by free energy calculation. The binding energy results show that the structurally optimized compounds (N1: −65.409 kcal mol−1, N3: −54.619 kcal mol−1, N4: −62.627 kcal mol−1, N5: −60.903 kcal mol−1, and N8: −66.272 kcal mol−1) have lower binding free energy values than compound 43 (ΔGbind: −49.991 kcal mol−1), indicating that they have a better affinity for the target. These findings provide necessary theoretical guidance for the discovery and design of highly active drugs against myocarditis. [ABSTRACT FROM AUTHOR]

3D-QSAR models were established using 52 compounds of pyrazolopyrimidine analogues with multiple substituents. We studied the relationship between molecular structure and inhibitory activity using comparative molecular field analysis (CoMFA), CoMFA region focusing (CoMFA-RG), and comparative molecular similarity index (CoMSIA). The results showed the model established by CoMFA-RG method was the optimal model, and its internal cross-validation correlation coefficient (q2 = 0.703) and non-cross-validation correlation coefficient (r2 = 0.981) had good statistical significance. Ten newly designed compounds were designed and their ADME/T properties were tested based on contour maps. Molecular docking method was used to analyze the interaction between compound 31 and IRAK4. At the same time, it also showed the binding mode of the new compounds to IRAK4 was the same as the compound 31; the hydrogen bond and hydrophobic bond played important roles in the binding process. Molecular dynamics simulation results showed residues Met192, Tyr262, Met265, Asp278, and Ala315 played vital roles of compounds to IRAK4. Combined DFT and free energy analysis theoretically proved compound Des07 had higher inhibitory activity than compound 31. [ABSTRACT FROM AUTHOR]

Hsp90 is a highly conserved and essential stress protein located in all eukaryotes, involved in the regulation of fungal survival, virulence and resistance, which is an important target for the treatment of fungal infections. Here, we intended to discover a novel inhibitor against Hsp90 guided by theoretical 3-dimensional quantitative structure–activity relationship (3D-QSAR) models for aminopyrazole analogs, which were constructed by the comparative molecular field analysis (CoMFA) and the comparative molecular similarity index analysis (CoMSIA) models. The CoMFA (q2 = 0.708, R2 = 0.962) and CoMSIA (q2 = 0.656, R2 = 0.922) models had good stability and predictability, and their contour maps could provide 3D visual information for structural modification. Subsequently, all the inhibitors used in modeling were docked into the binding site of Hsp90 by the Surflex-Dock method and their interaction was explored, which indicated that inhibitor complexes to Hsp90 mainly relied on hydrogen bonds, Pi–S stacking and hydrophobic interactions. Then, we designed 10 novel candidates guided by contour maps and binding modes, and their potential anti-fungal activity and ADME/T profile were predicted by 3D-QSAR models and online tools, which showed the candidates with better potency and good ADME/T properties. We achieved the stable conformation of candidates (M7 and M9) complexed to Hsp90 by molecular dynamics (MD) simulations and evaluated their binding energy and energy contribution of amino acids by MM/PBSA. Compared to reports in the literature (compound 22: −44.725), the designed candidates (M7: −51.478, M9: −54.964) had better potency represented by binding energy. Based on the energy contribution of amino acids, we identified the key residues that interacted with candidates, such as Asp82, Thr174 and Leu37, which had a crucial role in increasing the binding affinity. Thus, our study could provide theoretical clues to design an inhibitor against Hsp90 which is used as an anti-fungal agent. [ABSTRACT FROM AUTHOR]

Antioxidant peptides play an important role in preventing the harmful effects of free radicals against human tissues, by inhibiting and delaying lipid oxidation. Plenty of peptides have been reported by recent literature. Tripeptides, one of the interesting antioxidants, have shown good antioxidant activity. Here, we collected 198 antioxidant tripeptides from literature and applied comparative molecular field analysis (CoMFA) and comparative similarity index analysis (CoMSIA) to construct three-dimension quantitative structure-activity relationship (3D-QSAR) models, which were used to guide combinations design and virtual screening for novel peptides. The CoMFA and CoMISA models had good predictability (R 2 : 0.735 vs 0.733) and stability (Q 2 : 0.885 vs 0.914). The contour maps indicated steric, electrostatic, hydrophilic and hydrogen bond acceptor force fields contributed greatly to the antioxidant activity, which could give directly and graphical information for rational design and modification of novel peptides. Consequently, we designed and synthesized 10 new tripeptides and tested their relative antioxidant activity by FRAP and ABTA methods. As a result, most of them showed good antioxidant effects. The high correlation between observed and predicted activity indicated a good predictability of our 3D-QSAR models, which could be used for the combinational design and virtual screening of antioxidant peptides. Image 1 • A three-dimensional QSAR was insight into the structure-activity relationship of antioxidant peptides. • Steric, electrostatic, hydrophobic and hydrogen bond acceptor took into account simultaneously. • Predicted antioxidant activities were consistent with observed values. • Novel peptides with promising activity designed, and were predicted biological activity by using built models. • Biological effects assay of novel tripeptides were performed to validate the reliability of 3D-QSAR. [ABSTRACT FROM AUTHOR]

• 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]

• 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]