DrugBank 6.0: the DrugBank Knowledgebase for 2024.

First released in 2006, DrugBank (https://go.drugbank.com) has grown to become the 'gold standard' knowledge resource for drug, drug-target and related pharmaceutical information. DrugBank is widely used across many diverse biomedical research and clinical applications, and averages more than 30 million views/year. Since its last update in 2018, we have been actively enhancing the quantity and quality of the drug data in this knowledgebase. In this latest release (DrugBank 6.0), the number of FDA approved drugs has grown from 2646 to 4563 (a 72% increase), the number of investigational drugs has grown from 3394 to 6231 (a 38% increase), the number of drug-drug interactions increased from 365 984 to 1 413 413 (a 300% increase), and the number of drug-food interactions expanded from 1195 to 2475 (a 200% increase). In addition to this notable expansion in database size, we have added thousands of new, colorful, richly annotated pathways depicting drug mechanisms and drug metabolism. Likewise, existing datasets have been significantly improved and expanded, by adding more information on drug indications, drug-drug interactions, drug-food interactions and many other relevant data types for 11 891 drugs. We have also added experimental and predicted MS/MS spectra, 1D/2D-NMR spectra, CCS (collision cross section), RT (retention time) and RI (retention index) data for 9464 of DrugBank's 11 710 small molecule drugs. These and other improvements should make DrugBank 6.0 even more useful to a much wider research audience ranging from medicinal chemists to metabolomics specialists to pharmacologists.

ROCK2 promotes ryanodine receptor phosphorylation and arrhythmic calcium release in diabetic cardiomyocytes.

BACKGROUND: Diabetes is associated with an increased risk of heart failure, cardiac arrhythmias and sudden cardiac death. We previously showed that ROCK2 expression is elevated in diabetic rat hearts, and that ROCK inhibition acutely improves their contractile function. In the present study we investigated whether inhibition of ROCK or partial deletion of ROCK2 improves impaired Ca2+ handling in the diabetic heart. METHODS: Contractile properties and Ca2+ transients were measured before and after treatment with the ROCK inhibitor Y-27632 (1 µM) in fluo-4-loaded cardiomyocytes isolated from streptozotocin (STZ)-diabetic or non-diabetic rats. Cardiac function was determined in vivo, and contractile properties and Ca2+ transients also measured in cardiomyocytes from non-diabetic and STZ-diabetic wild-type (WT) and ROCK2+/- mice. RESULTS: ROCK inhibition improved some parameters of contractile function and Ca2+ handling in cardiomyocytes from diabetic rat hearts. In addition, ROCK inhibition attenuated the diabetes-induced delayed aftercontractions (DACs) and associated irregular Ca2+ transients induced by increased [Ca2+]o. Although no overt cardiac dysfunction was detected in diabetic WT mice, cardiomyocytes from these mice also developed arrhythmic Ca2+ transients in response to increased [Ca2+]. These were attenuated in cardiomyocytes from diabetic ROCK2+/- mice, in association with decreased diastolic Ca2+ leak and with reduction of the diabetes-induced increased phosphorylation of both CaMKII and the ryanodine receptor (RyR). CONCLUSIONS: These data suggest that ROCK2 contributes to diabetes-induced impaired cardiac Ca2+ homeostasis, at least in part by promoting CaMKII-mediated phosphorylation of RyR. This may have important clinical implications for the treatment of the increased incidence of dysrhythmias in diabetes.

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction.

Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2(+/-) mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2(+/-), mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2(+/-) mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2(+/-), mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr(612), Akt, and AS160 was also impaired in these hearts, while Ser(307) phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2(+/-) mice, and cardiac levels of TNFα were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesity-induced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition.