Wenjuan Wu

Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T315I mutant, makes the search for new Abl T315I inhibitors a very interesting challenge in medicinal chemistry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics (MD) simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T315I. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T315I activities were designed and presented to experimenters for reference.

Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is a promising drug target to treat toxoplasmosis, and the selective TgCDPK1 inhibition over human kinases is significant for the development of potent antiparasitic TgCDPK1 inhibitors. In the present study, a total set of 46 pyrazolopyrimidine-based compounds possessing TgCDPK1 and Src inhibitory activity were studied by using a molecular modeling approach combining molecular docking, three dimensional quantitative structure–activity relationship (3D-QSAR) and molecular dynamics (MD) simulations. The best comparative molecular field analysis (CoMFA) models were established with satisfactory robustness and predictability, with R² = 0.968, q² = 0.666 and R_pred ² = 0.745 for TgCDPK1 and R² = 0.970, q² = 0.581 and R_pred ² = 0.635 for Src, respectively. Other tests on additional validations further confirmed the satisfactory predictive power of the models. The key residues impacting the interactions and the probable binding modes between inhibitor and enzymes (TgCDPK1 and Src) were identified by docking and further verified by MD simulations. Computational results demonstrated that bulky or electronegative substituents on R₂, and certain bulky groups attached to the terminal of R₁ may increase the potency of TgCDPK1 and TgCDPK1/Src selectivity. Finally, six new compounds showing high TgCDPK1 potency and TgCDPK1/Src selectivity were designed. We hope this study can be helpful for further development of novel potent TgCDPK1 selective inhibitors.

P2Y₁₂ receptor is an attractive target for the anti-platelet therapies, treating various thrombotic diseases. In this work, a total of 107 6-aminonicotinate-based compounds as potent P2Y₁₂ antagonists were studies by a molecular modeling study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations to explore the decisive binding conformations of these antagonists with P2Y₁₂ and the structural features for the activity. The optimum CoMFA and CoMSIA models identified satisfactory robustness and good predictive ability, with R² = .983, q² = .805, = .881 for CoMFA model, and R² = .935, q² = .762, = .690 for CoMSIA model, respectively. The probable binding modes of compounds and key amino acid residues were revealed by molecular docking. MD simulations and MM/GBSA free energy calculations were further performed to validate the rationality of docking results and to compare the binding modes of several compound pairs with different activities, and the key residues (Val102, Tyr105, Tyr109, His187, Val190, Asn191, Phe252, His253, Arg256, Tyr259, Thr260, Val279, and Lys280) for the higher activity were pointed out. The binding energy decomposition indicated that the hydrophobic and hydrogen bond interactions play important roles for the binding of compounds to P2Y₁₂. We hope these results could be helpful in design of potent and selective P2Y₁₂ antagonists.

An integrated computational study was performed to identify the binding mechanisms of benzamide-based derivatives with Abl_wt/Abl_T315I kinases for designing Abl inhibitors.

Potent dual NF-κB/AP-1 inhibitors could effectively treat immunoinflammatory diseases. An integrated computational study was carried out to identify the most favourable binding sites, the structural features and the interaction mechanisms.

Recently, the development of Src/Abl (c-Src/Bcr–Abl tyrosine kinases) dual inhibitors has attracted considerable attention from the research community for treatment of malignancies. In order to explore the different structural features impacting the Src and Abl inhibitory activities of N⁹-arenethenyl purines and to investigate the molecular mechanisms of ligand–receptor interactions, a molecular modeling study combining the three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations was performed. The obtained CoMFA (comparative molecular field analysis) models exhibited satisfactory internal and external predictability. The plots of the CoMFA fields could be used to investigate the structural differences between DFG-in (targeting the active enzyme conformation) and DFG-out (targeting the inactive enzyme conformation) inhibitors. The key amino acid residues were identified by docking studies, and the detailed binding modes of the compounds with different activities were determined by MD simulations. The binding free energies gave a good correlation with the experimental determined activities. In an energetic analysis, the MM-PBSA (molecular mechanics Poisson–Boltzmann surface) energy decomposition revealed that the van der Waals interactions were the major driving force for the binding of the DFG-in and DFG-out compounds to Src and Abl, especially the hydrophobic interactions between ligands and residues Ala403/380, Asp404/381, and Phe405/382 in DFG-out Src and Abl complexes. They also help to stabilize the DFG-out conformations. These results can offer useful references for designing novel potential DFG-in and DFG-out dual Src/Abl inhibitors.

In recent years, the development of dual or multi‐targeted inhibitors has captured extensive attention of research for treating of malignancies. In this paper, three‐dimensional quantitative structure‐activity relationship and docking studies were performed on 87 pyrazolo[3,4‐d]pyrimidines as dual Src/Abl inhibitors. The appropriate binding orientations and conformations of these compounds interacting with both Src and Abl kinases were revealed by docking studies, and the established optimum CoMFA models yielded q²=0.856, R²=0.966 for Src and q²=0.869, R²=0.974 for Abl, and the best CoMSIA models gave q²=0.877, R²=0.979 for Src and q²=0.885, R²=0.982 for Abl. Systemic external validations further confirm the satisfactory predictive power of these models, producing R²_pred values of 0.872 and 0.865 for Src, 0.876 and 0.867 for Abl, r²_m values of 0.832 and 0.928 for Src, 0.838 and 0.904 for Abl, respectively. In addition, through a comparison between 3D‐QSAR contour maps and docking results, it is revealed that the hydrophobic and electrostatic interactions of compounds play significant roles for the inhibitory activity against both Src and Abl kinases. Some structural factors influencing the activities of these compounds were discussed in detail. The key amino acids impacting the receptor‐ligand interactions have been identified. These theoretical results can offer useful references for designing novel potential dual Src/Abl inhibitors.

The development of selective lymphocyte‐specific kinase (Lck) inhibitors has attracted much attention for the research of the treatment of T‐cell mediated autoimmune and inflammatory diseases. In the present work, three‐dimensional quantitative structure–activity relationship (3D‐QSAR) analyses are performed on a novel series of 4‐amino‐6‐benzimidazole‐pyrimidines acting as Lck inhibitors. The established 3D‐QSAR models show significant statistical quality and satisfactory predictive ability, with high q² and R² values: the comparative molecular field analysis (CoMFA) model (q² = 0.802, R² = 0.991), and the comparative molecular similarity indexes analysis (CoMSIA) model (q² = 0.731, R² = 0.982). The systemic external validation indicates that both CoMFA and CoMSIA models are quite robust and possess high predictive abilities with values of 0.881 and 0.877, values of 0.897 and 0.847, values of 0.897 and 0.850, and values of 0.897 and 0.854, respectively. Several key structural features accounting for the inhibitory activities of these compounds are discussed. Based on established models and design considerations, six new compounds with significantly improved activities are theoretically designed, which still await experimental confirmation and evaluation. These theoretical results may provide a useful reference for understanding the action mechanism and designing novel potential Lck inhibitors.

All-atom molecular simulations and two-dimensional nuclear overhauser effect spectrum have been used to study the conformations of carnosine in aqueous solution. Intramolecular distances, root-mean-square deviation, radius of gyration, and solvent-accessible surface are used to characterize the properties of the carnosine. Carnosine can shift between extended and folded states, but exists mostly in extended state in water. Its preference for extension in pure water has been proven by the 2D nuclear magnetic resonance (NMR) experiment. The NMR experimental results are consistent with the molecular dynamics simulations.