Hsp90 is involved in correcting, folding, maturation and activation of a diverse array of client proteins; it has also been implicated in the treatment of cancer in recent years. In this work, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), molecular docking and molecular dynamics were performed on three different series of Hsp90 inhibitors to build 3D-QSAR models, which were based on the ligand-based or receptor-based methods. The optimum 3D-QSAR models exhibited reasonable statistical characteristics with averaging internal q² > 0.60 and external r²_pred > 0.66 for Benzamide tetrahydro-4H-carbazol-4-one analogs (BT), AT13387 derivatives (AT) and Dihydroxylphenyl amides (DA). The results revealed that steric effects contributed the most to the BT model, whereas H-bonding was more important to AT, and electrostatic, hydrophobic, H-bond donor almost contributed equally to the DA model. The docking analysis showed that Asp93, Tyr139 and Thr184 in Hsp90 are important for the three series of inhibitors. Molecular dynamics simulation (MD) further indicated that the conformation derived from docking is basically consistent with the average structure extracted from MD simulation. These results not only lead to a better understanding of interactions between these inhibitors and Hsp90 receptor but also provide useful information for the design of new inhibitors with a specific activity.

Angiotensin-I-converting enzyme (ACE) is a key enzyme in the regulation of peripheral blood pressure and electrolyte homeostasis. Therefore, ACE is considered as a promising target for treatment of hypertension. In the present work, in order to investigate the binding interactions between ACE and tri-peptides, three-dimensional quantitative structure–activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were developed. Three different alignment methods (template ligand-based, docking-based, and common scaffold-based) were employed to construct reliable 3D-QSAR models. Statistical parameters derived from the QSAR models indicated that the template ligand-based CoMFA (R_cv ² = 0.761, R_pred ² = 0.6257) and CoMSIA (R_cv ² = 0.757, R_pred ² = 0.6969) models were better than the other alignment-based models. In addition, molecular docking studies were carried out to predict the binding modes of the peptides to ACE. The peptide–enzyme interactions were consistent with the derived 3D contour maps. Overall, the insights gained from this study would offer theoretical references for understanding the mechanism of action of tri-peptides when binding to ACE and aid in the design of more potent tri-peptides.

Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase competitive inhibitors, not only lower blood cholesterol, but also exert pleiotropic and beneficial effects in various diseases. However, the effects of statins on acute lung injury (ALI) induced by hyperbaric oxygen (HBO) have not been investigated. The present study is the first to investigate the effects of simvastatin in ALI induced by HBO in 8 - 9 week old C57BL/6 mice exposed to 0.23 MPa (= 2.3 atmosphere absolute (ATA)) hyperoxia ( 95% O2) for 6 hrs. Mice were either given simvastatin (20 mg/kg/day) in saline or a saline vehicle for 3 days before oxygen exposure. Lung tissue, serum, and bronchoalveolar lavage fluid (BALF) were collected for analysis of pro-apoptotic proteins, low-density lipoprotein cholesterol (LDL-C) levels, and lung inflammation. Simvastatin treatment significantly reduced lung permeability, serum LDL-C levels, tissue apoptosis, and inflammation. However, simvastatin treatment had no effect on antioxidant enzyme activity, nicotinamide adenine dinucleotide phosphate oxidase 4 (NADPH4) expression, and Akt phosphorylation levels. Furthermore, we investigated the role of endothelial nitric oxide synthase (eNOS) in simvastatin protection through inhibiting eNOS activity with NG-Nitro-L-arginine methyl ester (L-NAME; 20 mg/kg). Results showed that the beneficial effects of simvastatin on ALI induced by HBO (anti-inflammatory, anti-apoptotic, lipid-lowering, and reduction in lung permeability) were reversed. These results showed that simvastatin curbs HBO-induced lung edema, permeability, inflammation, and apoptosis via upregulating eNOS expression, and that simvastatin could be an effective therapy to treat prolonged HBO exposure.

The vascular endothelial growth factor receptor-2 kinases (VEGFR-2) expressed on tumor cells and vessels are attractive targets for cancer treatment. Potent inhibitors for the VEGFR-2 receptor are novel strategies to develop anti-cancer drugs. In this work, template ligand-based 3D-QSAR studies were performed on a series of benzoxazole derivatives toward different cell lines (HepG2, HCT-116 and MCF-7). Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques were used to generate 3D-QSAR models. Good predictability was derived for the optimal CoMFA models (HepG2: R_cv ² = 0.509, R_pred ² = 0.5128; HCT-116: R_cv ² = 0.574, R_pred ² = 0.5597; MCF-7: R_cv ² = 0.568, R_pred ² = 0.5057) and CoMSIA models (HepG2: R_cv ² = 0.711, R_pred ² = 0.6198; HCT-116: R_cv ² = 0.531, R_pred ² = 0.5804; MCF-7: R_cv ² = 0.669, R_pred ² = 0.6577). In addition, the contour maps derived from CoMFA and CoMSIA models were also generated to illustrate the relationship between different fields and the inhibitory activities. Moreover, molecular docking and molecular dynamics (MD) simulations were also conducted to understand the binding modes and the potential interactions between the receptor and the inhibitors. Some key residues (Leu35, Val43, Lys63, Leu84, Gly117, Leu180 and Asp191) were pointed out for stabilizing the inhibitors in the binding pocket. The binding free energies for the inhibitors agreed well with the experimental inhibitory activity and indicated that steric, electrostatic and hydrogen bond interactions are the main driving force for inhibitor-receptor binding. Overall, a good consistency between theoretical 3D-SQAR and molecular docking and MD simulation studies would provide directions for the design of new candidates, avoiding time-consuming and costly synthesis and biological evaluations. On the whole, the results derived from this study could expand the understanding of benzoxazole derivatives as anticancer agents and would be of great help in lead optimization for early drug discovery of highly potent anticancer activity targeting VEGFR-2.

Thyroid hormone (TH) possesses the ability to lower cholesterol and improve cardiac performance, which have prompted the efforts to design analogs that can utilize the cholesterol-lowering property without adversely affecting heart function. In order to gain insights into the interaction mechanism for agonists at the active site of thyroid hormone receptor β (TRβ), quantitative structure–activity relationship (QSAR) models have been developed on TRβ agonists, significant statistical coefficients were obtained (CoMFA, R²_cv, .732), (CoMSIA, R²_cv, .853), indicating the internal consistency of the models, the obtained models were further validated using the test set, the acquired R²_pred values .7054 and .7129 were in good agreement with the experimental results. The key amino acids affecting ligand binding were identified by molecular docking, and the detailed binding modes of the compounds with different activities were also determined. Furthermore, molecular dynamics (MD) simulations were conducted to assess the reliability of the derived models and the docking results. Moreover, TH exerts significant physiological effects through modulation of the two human thyroid hormone receptor subtypes. Because TRβ and TRα locate in different target cells, selective TR ligands would target specific tissues regulated by one receptor without affecting the other. Thus, the 3D information was analyzed to reveal the most relevant structural features involved in selectivity. The findings serve as the basis for further investigation into selective TRβ/TRα agonists.