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In order to better understand the biochemical interactions governing their activities in lowering blood pressure, multiple quantitative structure-activity relationship (QSAR) models were developed from a data set of 58 angiotensin converting enzyme (ACE) inhibitors. The models were built by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The best CoMFA model had a cross-validation q2 value of 0.940, a non cross-validation r2 value of 0.952 and an external validation statistic Qext 2 value of 0.920. For the best CoMSIA model the values were with q2 = 0.872, r2 = 0.926 and Qext 2 = 0.868. Based on the contour maps, eight new ACE inhibitors were designed. Molecular docking was employed to further explore the binding requirements between the ligands and the receptor protein which included several hydrogen bonds between the ACE inhibitors and active site residues. This study showed extensive interactions between ACE inhibitors and residues of HIS383, GLU384, HIS513, TYR520 and LYS511 in the active site of ACE. The design of potent new inhibitors of ACE can get useful insights from these results.

In order to better understand the biochemical interactions governing their activities in lowering blood pressure, multiple quantitative structure-activity relationship (QSAR) models were developed from a data set of 58 angiotensin converting enzyme (ACE) inhibitors. The models were built by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The best CoMFA model had a cross-validation q² value of 0.940, a non cross-validation r² value of 0.952 and an external validation statistic Qext ² value of 0.920. For the best CoMSIA model the values were with q² = 0.872, r² = 0.926 and Qext² = 0.868. Based on the contour maps, eight new ACE inhibitors were designed. Molecular docking was employed to further explore the binding requirements between the ligands and the receptor protein which included several hydrogen bonds between the ACE inhibitors and active site residues. This study showed extensive interactions between ACE inhibitors and residues of HIS383, GLU384, HIS513, TYR520 and LYS511 in the active site of ACE. The design of potent new inhibitors of ACE can get useful insights from these results. [ABSTRACT FROM AUTHOR]

The ionic-interactions of acetic acid in H2O–PVOH and H2O–alcohol– PVOH solvent systems were studied at different temperatures by the viscosity method. The viscosities of the poly(vinyl alcohol) (PVOH) were increased with increasing concentration of PVOH and decreased with the increasing concentration of acetic acid. The viscosity data were used to evaluate the ion–ion interactions and ion–solvent interactions in terms of the A and B coefficients of the Jones–Dole equation, respectively. The negative values of the B-coefficient increased with increasing temperature, showing that the acid behaves as a structure breaker in PVOH–solvent mixtures and consequently, the values of the A-coefficient were decreased with increasing temperature. Thermodynamic parameters, such as energy of activation (Ea*), Gibbs energy change of activation (ΔG*) and entropy change of activation (ΔS*) were also calculated as a function of the acid (CH3COOH) concentration, PVOH composition, alcohols and temperature.

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Acquired immunodeficiency syndrome (AIDS) is a significant human health threat around the world and therefore, the study of anti-HIV drug design has become an important task for today's society. In this paper, a three-dimensional quantitative structure-activity relationships study (3D-QSAR) was conducted on 72 HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) using Topomer comparative molecular field analysis (Topomer CoMFA). The multiple correlation coefficients of fitting, cross-validation, and external validation were 0.899, 0.788 and 0.942, respectively. The results indicated that the obtained model had both a favorable estimation stability and a good prediction capability. Topomer Search was used to search appropriate R groups from the ZINC database, Thereby, 14 new compounds were designed, and 12 of the new compounds were predicted to be more active than the template molecule. These results strongly suggest that the Topomer search was effective in screening and could be a useful guide in the design of new HIV-1 drugs. The ligands of the template molecule and the new designed compounds were used for molecular docking to study the interaction of these compounds with the protein receptor. The results showed that the ligands would generally form hydrogen-bonding interactions with the residues Ala28, Asp29, Gly49 and Ile50 of the protein receptor, thereby providing additional insights for the designing of even more effective drugs. [ABSTRACT FROM AUTHOR]

Intermediate-conductance Ca2+-activated K+ (IK) channels are calcium/calmodulin-regulated voltage-independent K+ channels. Activation of IK currents is important in vessel and respiratory tissues, rendering the channels potential drug targets. A variety of small organic molecules have been synthesized and found to be potent activators of IK channels. However, the poor selectivity of these molecules limits their therapeutic value. Venom-derived peptides usually block their targets with high specificity. Therefore, we searched for novel peptide activators of IK channels by testing a series of toxins from spiders. Using electrophysiological experiments, we identified hainantoxin-I (HNTX-I) as an IK-channel activator. HNTX-I has little effect on voltage-gated Na+ and Ca2+ channels from rat dorsal root ganglion neurons and on the heterologous expression of voltage-gated rapidly activating delayed rectifier K+ channels (human ether-à-go-go-related gene; human ERG) in HEK293T cells. Only 35.2% ± 0.4% of the currents were activated in SK channels, and there was no effect on BK channels. We demonstrated that HNTX-I was not a phrenic nerve conduction blocker or acutely toxic. This is believed to be the first report of a peptide activator effect on IK channels. Our study suggests that the activity and selectivity of HNTX-I on IK channels make HNTX-I a promising template for designing new drugs for cardiovascular diseases.

In this paper, a three-dimensional quantitative structure-activity relationships study for 38 HIV-1 protease inhibitors was established using Topomer CoMFA. The multiple correlation coefficients of fitting, cross-validation, and external validation were 0.959, 0.867, and 0.964, respectively. The results indicated that the model obtained has both favorable estimation stability and good prediction capability. Topomer Search was used to search R-group from ZINC database. As the result, a series of R-groups with relatively high activity contribution was obtained. By No. 32 molecule filtering, 10 Ra and 6 Rb groups were selected. We employed the 10 Ra and 6 Rb groups to alternately substitutes for the Ra and Rb of sample 32. Finally, we designed 60 new compounds with higher activity than that of the template molecule. The results suggested the Topomer Search technology could be effectively used to screen and design new HIV-1 protease inhibitors and has good predictive capability to guide the design of new HIV/AIDS drugs. As the ligands, the training molecules and new designed compounds were used for molecular docking to study the interaction mode with the protein receptor. As the results, we found that the ligands would form the hydrogen-bonding interactions with Asp25, Asp29, Asp30, Gly48, and Ile50 of the protein receptor generally. [ABSTRACT FROM AUTHOR]

Intermediate-conductance Ca2+-activated K+ (IK) channels are calcium/calmodulinregulated voltage-independent K+ channels. Activation of IK currents is important in vessel and respiratory tissues, rendering the channels potential drug targets. A variety of small organic molecules have been synthesized and found to be potent activators of IK channels. However, the poor selectivity of these molecules limits their therapeutic value. Venom-derived peptides usually block their targets with high specificity. Therefore, we searched for novel peptide activators of IK channels by testing a series of toxins from spiders. Using electrophysiological experiments, we identified hainantoxin-I (HNTX-I) as an IK-channel activator. HNTX-I has little effect on voltage-gated Na+ and Ca2+ channels from rat dorsal root ganglion neurons and on the heterologous expression of voltage-gated rapidly activating delayed rectifier K+ channels (human ether-à-go-go-related gene; human ERG) in HEK293T cells. Only 35.2% ± 0.4% of the currents were activated in SK channels, and there was no effect on BK channels. We demonstrated that HNTX-I was not a phrenic nerve conduction blocker or acutely toxic. This is believed to be the first report of a peptide activator effect on IK channels. Our study suggests that the activity and selectivity of HNTX-I on IK channels make HNTX-I a promising template for designing new drugs for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.