Theoretical models of staurosporine and analogs uncover detailed structural information in biological solution.

Staurosporine and its analogs (STA-analogs) are indolocarbazoles (ICZs) compounds able to inhibit kinase proteins in a non-specific way, while present antimicrobial and cytostatic properties. The knowledge of molecular features associated to the complexation, including the ligand shape in solution and thermodynamics of complexation, is substantial to the development of new bioactive ICZs with improved therapeutic properties. In this context, the empirical approach of GROMOS force field is able to accurately reproduce condensed phase physicochemical properties of molecular systems after parameterization. Hence, through parameterization under GROMOS force field and molecular simulations, we assessed STA-analogs dynamics in aqueous solution, as well as its interaction with water to probe conformational and structural features involved in complexation to therapeutic targets. The coexistence of multiple conformers observed in simulations, and confirmed by metadynamics calculations, expanding the conformational space knowledge of these ligands with potential implications in understanding the ligand conformational selection during complexation. Also, changes in availability to H-bonding concerning the different substituents and water can reflect on effects at complexation free energy due to variation at the desolvation energetic costs. Based on these results, we expect the obtained structural data provide systemic framework for rational chemical modification of STA-analogs.

Neuropharmacological assessment in mice and molecular docking of piperazine derivative LQFM212.

Piperazine derivatives are an attractive class of chemical compounds for the treatment of various mental illness. Herein, we demonstrated the synthesis of LQFM212, a piperazine derivative, behavioral evaluation in mice and computational studies. In neuropharmacological assessment, LQFM212 treatment at doses of 18, 54 or 162 µmol/kg increased the sleep duration in sodium pentobarbital-induced sleep test. LQFM212 at dose of 162 µmol/kg increased climbing time in the chimney test and decreased the number of squares crossed in the open field test, suggesting that LQFM212 in high doses reduces spontaneous movement. However, LQFM212 treatment at the doses of 18 or 54 µmol/kg increased the preference for the center of field which could be indicative of anxiolytic-like effects. In elevated plus maze and light-dark box tests, LQFM212 treatment altered all parameters observed that demonstrate anxiolytic-like activity. These effects were reversed by flumazenil, mecamylamine, WAY-100635 and PCPA, but not with ketanserin, showing that anxiolytic-like activity involve benzodiazepine site of GABAA receptor, nicotinic and serotonergic pathways. Molecular docking of LQFM212 showed that the ligand has more interactions with GABAA receptor than with 5-HT1A receptor. Despite the involvement of benzodiazepine site on anxiolytic-like effect of LQFM212, treatment with this compound did not alter cognitive function in the step-down avoidance test. In this sense, this piperazine derivative is a good prototype for treating anxiety disorders with putative mechanism of action.

DRD4 and SLC6A3 gene polymorphisms are associated with food intake and nutritional status in children in early stages of development.

Variants of dopamine system genes such as the DRD4 and the SLC6A3 genes may be involved in food intake regulation because the dopaminergic system influences food reward. We investigated an association of polymorphisms in the DRD4 (exon 3 VNTR) and SLC6A3 (3'UTR VNTR, rs2550948, rs2652511 and rs1048953) genes with food intake and nutritional status in children. This prospective cohort study recruited 359 children at birth. Dietary data and nutritional status were collected at 1 year, 3-4 years, and 7-8 years of age. The polymorphisms were analyzed using polymerase chain reaction based techniques. Food intake and nutritional status were compared among the different SNP genotypes. In the first year of life, DRD4.7R- children showed higher BMI Z-scores (P=.019) than the DRD4.7R+ cohort. At 3-4 years old, DRD4.7R- and SLC6A3.10R/10R children showed a higher intake of palatable foods (P=.024) and a higher waist circumference (P=.017). The rs1048953 SLC6A3 polymorphism was associated with average daily energy intake (P=.003) at 3-4 years and with a waist-to-height ratio of children at 7-8 years (P=.041). Carriers of high dopamine activity alleles of the VNTRs studied in DRD4 and SLC6A3 genes and carriers of T/T genotype of the variant rs1048953 SLC6A3 can present an increased risk for obesity related to overeating because high dopamine activity can increase the perceived incentive value of food reward.

Evaluation of UGT1A1 and SULT1A1 polymorphisms with lipid levels in women with different hormonal status.

BACKGROUND: Estrogens influence many physiological processes including cardiovascular health. Polymorphisms in phase I and II estrogen metabolism enzymes are associated with lipid levels in women. METHODS: A cross-sectional study was carried out with 269 postmenopausal women, 116 who received oral hormonal therapy (HT) (39-75 years) with estrogens or estrogens plus progestagen, 153 that did not receive any HT (38-85 years), and 155 premenopausal women (18-52 years). Polymorphisms in UGT1A1 (rs5839491) and SULT1A1 (rs1042028) were analysed by PCR-based methods. Adjusted lipid levels means were compared among genotypes by one-way analysis of variance, with corrections for multiple testing. RESULTS: The UGT1A1*28 polymorphism was associated with total cholesterol (T-chol) (p = 0.030; corrected p = 0.060) and low-density lipoprotein cholesterol (LDL-C) levels (p = 0.011, corrected p = 0.022) in premenopausal women. The premenopausal and postmenopausal women, both carriers of SULT1A1*2/*2, had lower levels of T-chol and LDL-C means than carriers of the SULT1A1*1/*1 (p = 0.004, corrected p = 0.008 and 0.009, corrected p = 0.018, respectively). CONCLUSION: The data showed the presence of an association between the UGT1A1*28/*28 and SULT1A1*2/*2 and T-chol and LDL-C levels in women with different hormonal status. No previous studies investigated the association of the polymorphisms examined in this study with lipoprotein levels in women separately by hormonal status.