Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis.

AIM: To explore the potent inhibitor from one of the Traditional Chinese medicine (TCM), Epimedium sagittatum. METHODS: We predicted the potent compound, ES03b, de novo evolution from the four Epimedium sagittatum components were verified by molecular docking, pharmacophore analysis, and analysis of quantitative structure-activity relationship (QSAR) model, which was constructed by multiple linear regression. RESULTS: ES03b was chosen to undergo drug modification via de novo evolution. By analyzing the pharmacophore features, we found that the hydrophobic core in the binding site and the hydrogen bond generated at Asn663 played key roles in designing PDE5 inhibitors. ES03b generated 49 diversities (Evo01-49). Evo48 had high activity in prediction. Although the value of prediction was overestimated, Evo48 was suggested as the potent lead. CONCLUSION: In this study, we showed that the hydrophobic core in the binding site and hydrogen bond production on Asn663 played key roles to design PDE5 inhibitors. From several require validation analysis, Evo48 was suggested to be a potent inhibitor.

Differential effects of dopamine D1 and D2 receptor antagonists on conditioned orienting behavior in the rat.

Brain dopamine (DA) systems are known to be important in regulation of behavior conditioned to appetitive stimuli. Nevertheless, despite a large body of evidence showing behavioral deficits in the operant conditioning paradigm produced by DA receptor blockade, there have been relatively few studies directly assessing behavioral changes in classical conditioning paradigm under this drug treatment. By employing an appetitive Pavlovian conditioning task, the present work investigated the effects of selective D1 and D2 receptor antagonists on the expression and acquisition of the conditioned orienting response (COR) and food-cup approach. SCH23390 (0, 0.05, and 0.10 mg/kg) and raclopride (0, 0.1, and 0.2 mg/kg) were administered via an intra-peritoneal route in a between-group design. Data from Experiment 1 showed that both SCH23390 and raclopride suppressed expression of the COR and food-cup approach, but only the impairment produced by raclopride reached a significant level. In Experiment 2, with SCH23390 being administered during the acquisition phase, the suppressed COR was completely restored in a subsequent (24 h later) drug-free session. In contrast, the suppressed COR in raclopride-pretreated groups was only partially restored. These findings support the view that the DA system plays a role in the neural substrates underlying this appetitive conditioning. In addition, D2 receptors are more likely involved in the modulation of learning process of the COR than D1 receptors.

Ligand-based dual target drug design for H1N1: swine flu--a preliminary first study.

In March and April, 2009, an outbreak of H1N1 influenza in Mexico had led to hundreds of confirmed cases and the death toll had risen to 160. The worldwide spread of H1N1 has been attracting global attention and arising an overwhelming fear. So far, the vaccine and remedy has been in urgent need. In this study, a QSAR model and pharmacophore map of neuraminidase (NA) type 1 (N1) contained two hydrogen bond acceptor features, one hydrogen bond donor feature, and one positive ionizable feature. NCI database was employed in virtual screen by the N1 pharmacophore map features. After screening, compounds were obtained and then docked into haemagglutinin type 1 (H1) to find out the candidate drugs for dual target of both N1 and H1. The candidate, NCI0353858, selected via virtual screening and docking, might be functional to this worldwide disease; consequently, further clinical investigations and scientific application are urgently demanded. We realize the proposed ligand does not have much validity without conducting a study on the stability of the protein-ligand complex by MD simulations and binding free energy, and such a study is underway and will be reported later in this journal. Nevertheless, the present study is clear, consistent and could give a rational explanation for the binding mode of the best selected ligand.