Gold Score Research Articles

Does Hypoglycemia Awareness Status on Gold and Clark Questionnaires Predict Hormonal and Symptomatic Responses to Hypoglycemia (HG) in Type 1 Diabetes (T1D)?

Impaired awareness of hypoglycemia (IAH) is characterized by the diminished ability to perceive symptoms of HG. Gold and Clark questionnaires are commonly used in research to identify patients with IAH. However, the relationship between IAH status on questionnaires and the symptom and counterregulatory (CR) hormone responses to HG are not well understood. In this study, we examined data from 51 research subjects with T1D who completed both questionnaires and underwent a hyperinsulinemic hypoglycemic clamp (target glucose 50 mg/dL) on the same day. Clarke and Gold scores were highly correlated with one another (r = 0.78) and each had a similar relationship with epinephrine (EPI) response during HG (Clarke: r = -0.46, Gold: r = -0.53) and symptom response (Clarke: r = -0.60, Gold: r = -0.52). However, Clarke and Gold disagreed on classification of HG awareness status (misclassification=37%, Cohen’s κ=0.54). Clarke classifications were: 26 Aware (A), 13 Indeterminate (I), 12 Unaware (U), whereas Gold classifications were 16 A, 15 I, and 20 U. A mixture model based clustering identified 3 patterns in joint EPI and symptom responses. Cluster 1 subjects (n=10) had low symptom (<5) and EPI responses (<140) to HG and 8/10 were classified as U by one or both questionnaires. Cluster 3 subjects (n=9) had high symptom (20+) and EPI responses (450+) to HG and 8 of 9 were classified as A by one or both questionnaires. Cluster 2 subjects (n=22) had intermediate symptom and EPI responses to HG but concordance of classification by Clarke and Gold was true for only 11 of the 24. Clarke classified cluster 2 subjects as 12 A, 7 I, and 3 U whereas Gold classified the same subjects into 6 A, 7 I, and 9 U. IAH classification may be discordant between Clark and Gold questionnaires and may not always correlate with the CR responses during experimental HG. To ensure reproducibility, researchers must be rigorous and consistent in defining the awareness status of study subjects. Disclosure N. Rubin: None. A. Moheet: None. L.E. Eberly: None. A. Kumar: None. S. Mangia: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..

Implications of sequence conservation patterns of serpin B family leading to structural and functional importance

SERine Proteinase INhibitors Clade B: SERPINS, a largely dispersed family of protease inhibitors that exhibit a conformational alteration to inhibit target enzymes. Atypical serpin proteins often form aggregates that can accumulate to toxic levels within cells. SerpinB4 is a chymotrypsin-like serine proteinase inhibitor. Phylogenetic analysis of Serpin Clade B revealed no duplication throughout the mammalian clades. Thus, elucidating retention of a single copy of human serpin members in nature, endorsing its essentiality as an inhibitor. Epidemiological studies specify that a rising number of patients are inclined to develop chronic liver disease due to SerpinB4 overexpression. This upregulation is therefore not in fine fettle for the human physiology. Molecular docking protocol classified compound 57, a novel inhibitory compound, as the ligand, best able to fit the binding pocket with a Gold Score of 94. A two hundred nanosecond molecular dynamics simulation of docked SerpinB4 illustrated a steady binding pattern of ligand in the protein's active site. Pursuing this, trajectory analysis was implemented to assess various characteristics of the docked system in terms of function of time. These findings may act effectively in designing effective remedies against SerpinB4.

Subtractive Genomics, Molecular Docking and Molecular Dynamics Simulation Revealed LpxC as a Potential Drug Target Against Multi-Drug Resistant Klebsiella pneumoniae

The emergence and dissemination of pan drug resistant clones of Klebsiella pneumoniae are great threat to public health. In this regard new therapeutic targets must be highlighted to pave the path for novel drug discovery and development. Subtractive proteomic pipeline brought forth UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase (LpxC), a Zn+2 dependent cytoplasmic metalloprotein and catalyze the rate limiting deacetylation step of lipid A biosynthesis pathway. Primary sequence analysis followed by 3-dimensional (3-D) structure elucidation of the protein led to the detection of K. pneumoniae LpxC (KpLpxC) topology distinct from its orthologous counterparts in other bacterial species. Molecular docking study of the protein recognized receptor antagonist compound 106, a uridine-based LpxC inhibitory compound, as a ligand best able to fit the binding pocket with a Gold Score of 67.53. Molecular dynamics simulation of docked KpLpxC revealed an alternate binding pattern of ligand in the active site. The ligand tail exhibited preferred binding to the domain I residues as opposed to the substrate binding hydrophobic channel of subdomain II, usually targeted by inhibitory compounds. Comparison with the undocked KpLpxC system demonstrated ligand induced high conformational changes in the hydrophobic channel of subdomain II in KpLpxC. Hence, ligand exerted its inhibitory potential by rendering the channel unstable for substrate binding.

Sustained Reduction in Severe Hypoglycemia in Adults With Type 1 Diabetes Complicated by Impaired Awareness of Hypoglycemia: Two-Year Follow-up in the HypoCOMPaSS Randomized Clinical Trial.

Severe hypoglycemia is a feared complication of type 1 diabetes; yet, few trials have targeted prevention using optimized self-management (educational, therapeutic, and technological support). We aimed to investigate whether improved awareness and reduced severe hypoglycemia, achieved during an intensive randomized clinical trial (RCT), were sustained after return to routine care. Ninety-six adults with type 1 diabetes (29 ± 12 years' duration) and impaired awareness of hypoglycemia at five U.K. tertiary referral diabetes centers were recruited into a 24-week 2 × 2 factorial RCT (HypoCOMPaSS). Participants were randomized to pump (continuous subcutaneous insulin infusion [CSII]) or multiple daily injections (MDIs) and real-time continuous glucose monitoring (RT-CGM) or self-monitoring of blood glucose (SMBG), with equal education/attention to all groups. At 24 weeks, participants returned to routine care with follow-up until 24 months, including free choice of MDI/CSII; RT-CGM vs. SMBG comparison continued to 24 months. Primary outcome was mean difference (baseline to 24 months [between groups]) in hypoglycemia awareness. Improvement in hypoglycemia awareness was sustained (Gold score at baseline 5.1 ± 1.1 vs. 24 months 3.7 ± 1.9; P < 0.0001). Severe hypoglycemia rate was reduced from 8.9 ± 12.8 episodes/person-year over the 12 months prestudy to 0.4 ± 0.8 over 24 months (P < 0.0001). HbA1c improved (baseline 8.2 ± 3.2% [66 ± 12 mmol/mol] vs. 24 months 7.7 ± 3.1% [61 ± 10 mmol/mol]; P = 0.003). Improvement in treatment satisfaction and reduced fear of hypoglycemia were sustained. There were no significant differences between interventions at 24 months. Optimized insulin replacement and glucose monitoring underpinned by hypoglycemia-focused structured education should be provided to all with type 1 diabetes complicated by impaired awareness of hypoglycemia.

Caring Together 2 Breathe Easy: an integrated care trial to reduce readmission and improve the health care experience for people with COPD

Introduction: As evidenced in “Perils of Place – Identifying hotspots of health inequality” (Duckett, 2016), Caboolture (Queensland) was highlighted as having a 10 year history of higher than average readmission rates for patients with Chronic Obstructive Pulmonary Disease (COPD). A new Integrated Pathway of Care is being trialled for COPD patients (n=30). Key collaborators include: the Caboolture Hospital Emergency Department and Respiratory Service; GP practices, Queensland Ambulance Service and key community services. The model of care, known as Caring Together 2 Breathe Easy was developed in collaboration with Canterbury Health in New Zealand. This model employs a patient focus to improve QoL by implementing COPD Action Plans and ensuring that the patient, their GP, Ambulance and the Emergency Department utilise this plan, including alternatives for acute care. A “Breathe Easy” team: GPLO, Clinical Nurse; Physiotherapist and Psychologist, work with the participants to implement action and intervention plans. Participants are provided with a pack which includes their COPD action plan, contact plan and educational materials. Aims and Measures: Reduced ED presentations and re-admission rate within 28 days Improved QoL measured by COPD Assessment Tool (CAT) and meeting individual goals Identification of secondary anxiety and depression (K-10) and linkage to supports Improved GOLD Score Increased access and connection to health and community services Developing integrated pathways with health and community services. Targeted Population and Stakeholders: Patients with a diagnosis of COPD and a history of re-presentations and/or re-admissions to the Caboolture Hospital within 28 day within the past two years (N=30) Participants reside in the Caboolture community which has recognised unmet health needs and high levels of socioeconomic disadvantage (Source: The Social Health of Australia: Data by population area, Population Health Information Data Unit 2016) Timeline 2017: Feb: Cohort selected March- April: Recruitment, Assessments May-Jun: Action Plans July-October: Interventions Nov-Dec: Evaluation Highlights: COPD Action Plans developed for all patients; High levels of consumer engagement with Breathe Easy Team and Project; Interventions commenced; Improved engagement and co-operation across secondary hospital, primary care, ambulance and community agencies. Sustainability: The intention is to upscale and embed the “Breathe Easy” pathway trial at an organisational and local community level. Transferability: If successful, the “Breathe Easy” trial outcomes will contribute to models of integrated care that can be applied to a range of patient groups requiring integrated care. Conclusions: Caboolture Hospital “Breathe Easy” project is demonstrating high levels of engagement and support from consumers, health care providers and the community. The multi-level evaluation data will provide evidence and inform viability for up-scaling and consolidation as an alternative health care service model in Caboolture and more broadly in Metro North HHS.

Discovery of novel drug candidates for inhibition of soluble epoxide hydrolase of arachidonic acid cascade pathway implicated in atherosclerosis

Soluble epoxide hydrolase (sEH), a key enzyme belonging to cytochrome P450 pathway of arachidonic acid cascade is a novel therapeutic drug target against atherosclerosis. The enzyme breaks down epoxyeicosatrienoic acid (EETs) to dihydroxy-eicosatrienoic acids (DHETs) and reduces beneficial cardiovascular properties of EETs. Thus, the present work is aimed at identification of potential leads as sEH inhibitors which will sustain the beneficial properties of EETs in vivo. PubChem and ZINC databases were screened for drug-like compounds based on Lipinski’s rule of five and in silico toxicity filters. The binding potential of the drug-like compounds with sEH was explored using molecular docking. The top ranked lead (ZINC23099069) showed higher GOLD score compared with that of the control, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid butyl ester (AUDA-BE) and displayed two hydrogen bonds with Tyr383 and His420 and eleven residues involved in hydrophobic interactions with sEH. The apo_sEH and sEH_ZINC23099069 complex showed stable trajectories during 20 ns time scale of molecular dynamics (MD) simulation. Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) binding free energy analysis showed that electrostatic energy is the driving energy component for interaction of the lead with sEH. These results demonstrate ZINC23099069 to be a promising drug candidate as sEH inhibitor against atherosclerosis instead of the present urea-based inhibitors.

The role of joint working between primary and secondary care in supporting people with type 1 diabetes

The role of joint working between primary and secondary care in supporting people with type 1 diabetes

Fear of hypoglycaemia and its relation to hypoglycaemia awareness and symptom intensity in Type 1 diabetes

AimsTo investigate fear of hypoglycaemia (FoH) in relation to hypoglycaemia awareness, history of severe hypoglycaemia (SH) and hypoglycaemia symptoms in adults with Type 1 diabetes. MethodsQuestionnaire-based cross-sectional survey. We assessed FoH with the Hypoglycaemia Fear Survey-II Worry subscale, hypoglycaemia awareness status with the Gold score, and used the Edinburgh Hypoglycaemia Scale to grade the presence and intensity of hypoglycaemia symptoms. All these measures have previously been validated for research application. We used multivariable linear regression to examine associations between FoH and hypoglycaemia awareness status, history of SH and hypoglycaemia symptom score. ResultsOf 636 invitees, 445 (70%) responded, with 435 responses eligible for analyses. Seventy-four persons had IAH (17%). Among those, 47 (64%) reported ≥ 1 SH during the preceding year, in contrast to this being reported by 113 (31%) of persons with normal awareness. The mean (SD) FoH worry score was 1.33 (0.78). This score was 0.64 (95% CI, 0.45–0.83) higher among people with impaired vs. normal hypoglycaemia awareness and 0.53 (95% CI, 0.33–0.73) higher among people with ≥ 3 episodes of SH the preceding year vs. people with no such episode. A higher number and intensity of hypoglycaemia symptoms was associated with higher FoH, as demonstrated by an increase in mean FoH worry score of 0.30 (95% CI, 0.23–0.36) per point increase in mean Edinburgh hypoglycaemia score. ConclusionsImpaired awareness of hypoglycaemia, history of SH and higher Edinburgh hypoglycaemia scores were all associated with increased FoH in adults with Type 1 diabetes.

A randomized controlled pilot study of continuous glucose monitoring and flash glucose monitoring in people with Type 1 diabetes and impaired awareness of hypoglycaemia

AimHypoglycaemia in Type 1 diabetes is associated with mortality and morbidity, especially where awareness of hypoglycaemia is impaired. Clinical pathways for access to continuous glucose monitoring (CGM) and flash glucose monitoring technologies are unclear. We assessed the impact of CGM and flash glucose monitoring in a high‐risk group of people with Type 1 diabetes.MethodsA randomized, non‐masked parallel group study was undertaken. Adults with Type 1 diabetes using a multiple‐dose insulin‐injection regimen with a Gold score of ≥ 4 or recent severe hypoglycaemia were recruited. Following 2 weeks of blinded CGM, they were randomly assigned to CGM (Dexcom G5) or flash glucose monitoring (Abbott Freestyle Libre) for 8 weeks. The primary outcome was the difference in time spent in hypoglycaemia (below 3.3 mmol/l) from baseline to endpoint with CGM versus flash glucose monitoring.ResultsSome 40 participants were randomized to CGM (n = 20) or flash glucose monitoring (n = 20). The participants (24 men, 16 women) had a median (IQR) age of 49.6 (37.5–63.5) years, duration of diabetes of 30.0 (21.0–36.5) years and HbA1c of 56 (48–63) mmol/mol [7.3 (6.5–7.8)%]. The baseline median percentage time < 3.3 mmol/l was 4.5% in the CGM group and 6.7% in the flash glucose monitoring. At the end‐point the percentage time < 3.3 mmol/l was 2.4%, and 6.8% respectively (median between group difference −4.3%, P = 0.006). Time spent in hypoglycaemia at all thresholds, and hypoglycaemia fear, were different between groups, favouring CGM.Conclusion CGM more effectively reduces time spent in hypoglycaemia in people with Type 1 diabetes and impaired awareness of hypoglycaemia compared with flash glucose monitoring. (Clinical Trial Registry No: NCT03028220)

Evaluating the relationships of hypoglycaemia and HbA1c with screening-detected diabetes distress in type 1 diabetes.

SummaryAimsTo explore the relationship between diabetes distress, glucose control and awareness of hypoglycaemia in adults with type 1 diabetes.MethodsWe performed a cross‐sectional study using data collected from 280 consecutive type 1 diabetes patients who used a routine clinic consultation tool that recorded HbA1c, hypoglycaemia awareness (measured using the Gold score) and diabetes distress (measured using the Diabetes Distress Scale 2 [DDS2]). We assessed correlations between DDS2 and HbA1c and DDS2 and Gold score and performed an ordinal regression analysis to identify factors contributing to distress.ResultsDiabetes distress was significantly correlated with HbA1c (r = .319, P < .001) and Gold score (r = .258, P < .001) independently and with synergistic effect. Female gender was also associated with diabetes distress, while age, BMI, duration of diabetes, severity of complications and use of CSII pumps were not. Occurrence of severe hypoglycaemia (SH) episodes increased with Gold score in a linear manner throughout the scale.ConclusionsThis study has identified new evidence of a significant, independent relationship between diabetes distress measured by the DDS2 and reduced awareness of hypoglycaemia in people with type 1 diabetes. It also demonstrates that diabetes distress is significantly associated with HbA1c and female gender independently. The DDS2 identifies distress associated with both hypo‐ and hyperglycaemia and can be a useful creening tool. Additionally, the occurrence of SH increases with increasing Gold score.

IN-SILICO SCREENING AGAINST ANTIMALARIAL TARGET PLASMODIUM FALCIPARUM ENOYL-ACYL CARRIER PROTEIN REDUCTASE

Objective: Malaria is a parasitic infection that causes worldwide health problems. The absence of an effective vaccine and Plasmodium strains that are resistant to antimalarial drugs emphasize the importance of developing new chemotherapeutic agents. The use of computers for in-silico screening, or virtual screening, is currently being developed as a method for discovering antimalarial drugs. One of the enzymes that can support the development of the malaria parasite is the Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR). Inhibition of these enzymes leads to Type II lipid biosynthesis inhibition on the parasite.Methods: This research investigates the use of virtual screening to find PfENR inhibitor candidates. A molecular docking method using GOLD software and the medicinal plants in Indonesia database will be used. This target has been optimized by the removal of residues and the addition of charge. Ligand is expected to be an inhibitor of PfENR.Results: In-silico screening, or virtual screening, found that the top five compounds with the highest GOLD score at trial are kaempferol 3-rhamnosyl- (1-3)-rhamnosyl-(1-6)-glucoside; cyanidin 3,5-di-(6-malonylglucoside); 8-hydroxyapigenin 8-(2’’, 4’’-disulfato glucuronide); epigallocatechin 3,5,-di- O-gallat; quercetin 3,4’-dimethyl ether 7-alpha-L-arabinofuranosyl-(1-6)-glucoside. They had GOLD scores of 94.73, 95.90, 86.46, 85.39, and 84.40, respectively.Conclusions: There are two candidate inhibitor compounds from tea (Camellia sinensis), which have potential for development as an antimalarial drug, which are kaempferol 3-rhamnosyl-(1-3)-rhamnosyl-(1-6)-glucoside and epigallocatechin 3,5,-di-O-gallate, with a GOLD score of 94.73 and 85.39, respectively.

IN SILICO SCREENING OF ANTIMALARIAL FROM INDONESIAN MEDICINAL PLANTS DATABASE TO PLASMEPSIN TARGET

Objective: Malaria is a disease that impacts millions of people annually. Among the enzymes, plasmepsin is the main enzyme in the plasmodium life cycle that degrades hemoglobin during the erythrocytic phase in the food vacuole. Recently, pharmaceutical industries have been trying to develop therapeutic agents that can cure malaria through the discovery of new plasmepsin inhibitor compounds. One of the developing approaches is the in silico method.Methods: The chosen in silico screening method in this experiment is a structure-based screening using GOLD software and the Indonesian medicinal plants database.Results: From ten in silico screening runs, three of the compounds always ranked in the top ten. These three compounds are trimyristin, cyanidin 3,5-di-(6-malonylglucoside), and isoscutellarein 4’-methyl ether 8-(6”-n-butylglucuronide). Another compound that emerged with high frequency is cyanidin 3,5-di-(6-malonylglucoside). Conclusions: Based on the results obtained from this screening, 11 inhibitor candidates are expected to be developed as antimalarial. These compounds are trimyristin; cyanidin 3,5-di-(6-malonylglucoside); isoscutellarein 4’-methyl ether 8-(6”-n-butylglucuronide); cyanidin 3-(6”-malonylglucoside)-5- glucoside; multifloroside; delphinidin 3-(2-rhamnosyl-6-malonylglucoside); delphinidin 3-(6-malonylglucoside)-3’,5’-di-(6-p-coumaroylglucoside); cyanidin 3-[6-(6-sinapylglucosyl)-2-xylosylgalactoside; kaempferol 3-glucosyl-(1-3)-rhamnosyl-(1-6)-galactoside; sanggenofuran A; and lycopene with a GOLD score range from 78.4647 to 98.2836. Two of them, Asp34 and Asp214, bind with all residues in the catalytic site of plasmepsin.

In silico identification of novel antagonists and binding insights by structural and functional analyses of guanylate kinase of Leishmania donovani and interaction with inhibitors

Guanylate kinase (GK; EC 2.7.4.8) is an important enzyme which catalyzed the ATP-dependent phosphorylation of GMP (guanosine monophosphate) into GDP (guanosine diphosphate) for survival of parasites; this suggests that it is a good target for design inhibitor(s). Knowledge of 3D structure of GKLdv is essential for elucidating interaction studies with the inhibitors and compared with substrate binding pattern in both the built model and template structures. The final reliable model of GKLdv has revealed α/β type protein with a G-X2-G-X-G-K that has a catalytic conserved domain in both template and model structure. The core domain consists of a central five-stranded parallel β-sheet (β5, β6, β3 and β4) whereas model has both α1-α10 and β1-β9 and active sites consist of flexible loop (FL1 to FL3). The superimposition structure of main-chain atoms of the GK model with closely homologue of GK (1EX7, chain A), has revealed better alignment and its root mean square deviation (RMSD) (43% similarity) is 0.602Ǻ. The virtual screening result has suggested that the binding pocket interacts with 5GP (5′-guanylic acid) with exhibited higher score in both GOLD and LigandFit scores and involve in amino acid interaction (H-bonding) are Arg40, Try80, Tyr52, Ser36, Glu71, and Asp102. The reported antileishmanial diospyrin (IC₅₀-7.2μM) has also exhibited higher binding activities (Dock score - 49.314 and Fitness score - 52.69) with frequently involved amino acids are Arg45, Glu102, Tyr35, Tyr54, Ser38, Tyr82, Ile103, Asp104, Lys106, Lys18, Pro13 and Ser14. The sigma pi interaction between Ile103 with diospyrin ring has revealed greater stable complex after molecular dynamic simulation studies. The best scoring compounds need for further validation in-vitro test.

In silico approaches to explore structure of new GPR 119 agonists for treatment of type 2 diabetes mellitus

The G protein coupled receptor 119 is an exciting and promising target for the treatment of type 2 diabetes mellitus. In this study, three dimensional quantitative structure activity relationships i.e. a comparative molecular field analysis and comparative molecular field analysis region focusing have been carried out on a novel series of G protein coupled receptor 119 agonists. A quality pharmacophore model was built by Hip-Hop algorithm. The best pharmacophore model indicated which feature of hydrogen-bond acceptor and hydrophobic existed around active compounds. As the quality of the pharmacophore model is satisfactory, it was utilized to search the ZINC database for a virtual screening task. The obtained compounds subjected to Lipinski filter at first, were docked with Gold algorithm to discover potent hits. The energy difference between the highest occupied molecular orbital and lowest unoccupied molecular orbital (“gap”) implies high reactivity of the most active molecule in the active site of protein. In addition, the molecular electrostatic potential energy at density functional theory level confirms the results from molecular docking. In silico absorption, distribution, metabolism, and excretion and toxicity risk assessment analysis were carried out on the seven hits with the highest Gold score fitness. Six of the new hits from virtual screening had diverse structures and are reported as new scaffold candidates for G protein coupled receptor 119 agonists.

IN SILICO MOLECULAR DOCKING AND PHARMACOKINETIC PREDICTION OF GALLIC ACID DERIVATIVES AS PPAR-γ AGONISTS

&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;To perform molecular docking and pharmacokinetic prediction of gallic acid derivatives as Peroxisome proliferator-activated receptors-γ (PPAR-γ) agonist for the treatment of diabetes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Molecular docking study on gallic acid and different derivatives of gallic acid was performed using GOLD v5.2 software. In addition to this, all the derivatives were analysed for drug likeliness, Lipinski’s rule and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties using online tools like admet SAR, Molinspiration and Medchem designer.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Molecular docking studies reveals that SSP-12, SSP-13 and SSP-40 demonstrated significant binding to the PPAR-γ receptor with good Gold score fitness (73.11, 69.86 and 75.51 respectively) and relative ligand energy (-8.26,-8.33 and-7.82, respectively) as compared to standard drugs i.e. rosiglitazone and pioglitazone, (64.10 and 66.72) and (-4.30 and-2.47) respectively.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The final results of molecular docking along with information gathered from pharmacokinetic parameters of gallic acid derivatives may be utilised further for the development of newer PPAR-γ agonists having anti-diabetic potential with better pharmacokinetic and pharmacodynamic profile.&lt;/p&gt;

Identification of novel drug candidate against Mycobacterium Tuberculosis InhA protein through Computer aided drug discovery

Tuberculosis is a common and often deadly infectious disease caused by Mycobacteria. WHO estimates that around eight million people are suffering from tuberculosis every year. The Administration of antibiotics fails due to the multi-drug resistant capability of Mycobacterium. Traditional methods require time and huge investment. Therefore, it is essential to provide an alternative strategy to treat tuberculosis disease. The present study conducted molecular docking against InhA protein, which is a potential target of tuberculosis disease. After docking with 1200 ligand molecule, 30 hits were selected based on the GOLD score. Finally, five potential hits were identified after redocking. The hydrogen bonding pattern, Lipinski’s rule, and drug likeliness were also checked for their potentiality as suitable drug candidates. We believe that our study will facilitate the selection of InhA as a potential target and selected hits as successful drug candidates for tuberculosis diseases. (Less)

Effectiveness of HypoAware, a Brief Partly Web-Based Psychoeducational Intervention for Adults With Type 1 and Insulin-Treated Type 2 Diabetes and Problematic Hypoglycemia: A Cluster Randomized Controlled Trial.

To establish the effectiveness of a brief, partly web-based group intervention, HypoAware, in patients with problematic hypoglycemia, in terms of the reduction of severe hypoglycemic episodes, impaired hypoglycemia awareness, and worries. A two-arm, cluster randomized controlled trial was conducted in insulin-treated patients with problematic hypoglycemia in eight Dutch clinics comparing HypoAware with care as usual. Primary outcomes included self-reported severe hypoglycemia, impaired hypoglycemia awareness (Gold score), and worries and distress about hypoglycemia (Hypoglycemia Fear Survey-II/Problem Areas In Diabetes scale hypo-item), assessed at baseline, and at 2, 4, and 6 months of follow-up. We used t tests, nonparametric tests, and intention-to-treat generalized estimation equation (GEE) analyses with linear, logistic, and Poisson or negative binomial models. We enrolled 137 participants. Adjusted GEE analyses over four time points showed a nonsignificant 33% fewer episodes of severe hypoglycemia in the HypoAware group compared with the control group (relative risk [RR] 0.67 [95% CI 0.39-1.16], P = 0.150); a significant reduced odds of impaired awareness (odds ratio 0.38 [95% CI 0.15-0.95], P = 0.038), a trend toward 20% fewer worries about hypoglycemia (RR 0.80 [95% CI 0.64-1.01], P = 0.059), and a significant 30% less hypo-distress (RR 0.70 [95% CI 0.56-0.88], P = 0.002). Over the 6-month study duration, participants experienced a median of 2.5 events of severe hypoglycemia (interquartile range [IQR] 1-10) in the control condition versus 1 event (IQR 0-6.5) in the HypoAware group (P = 0.030). There was no significant change in HbA1c level within and between both groups. HypoAware resulted in fewer severe hypoglycemic episodes, significantly improved hypoglycemia awareness, and less hypo-distress in comparison with usual care, and deserves further dissemination.

Synthesis and Docking Analysis of New Heterocyclic System N1, N4-bis (2-chloroquinolin-3-yl) methylene) benzene-1, 4-diamine as Potential Human AKT1 Inhibitor.

In recent years, the chemistry of 2-chloroquinoline-3-carbaldehydes have received considerable attention owing to their synthetic and effective biological importance which exhibits a wide variety of biological activity, N1,N4-bis((2-chloroquinolin-3-yl)methylene)benzene-1,4-diamine derivatives that synthesized from 2-chloroquinoline-3-carbaldehydes may have biological effects. As the inhibitor of AKT1 (RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1), the aforementioned compounds may have implication in preventing complications of cancers. A group of N1, N4-bis ((2-chloroquinolin-3-yl) methylene) benzene-1, 4-diamine derivatives (3a-3i) (H, 6-Me, 6-OMe, 6-OEt, 6-Cl, 7-Me, 6-Et, 6-Isopropyl, 7-Cl) were synthesized, and theoretically evaluated for their inhibitory as Potential Human AKT1 Inhibitors via docking process. The docking calculation was done in GOLD 5.2.2 software using Genetic algorithm. Compounds 3b (6-Me) and 3d (6-OEt) showed the best inhibitory potency by GOLD score value of 113.76 and 107.58 respectively. Some of the best models formed strong hydrogen bonds with Asn 49, Lys 220, Ser 157, Arg 225 and Trp 76 via quinoline moiety and nitrogen of quinolone ring (Figure 1.). pi-pi interaction between Lys 220, Trp 76, Tyr 224, Arg 225, Ile 80, and Asn 49 quinoline moiety was one of the common factor in enzyme-inhibitor junction. It was found that both hydrogen bonding and hydrophobic interactions are important in function of biological molecules, especially for inhibition in a complex.

Targeting cytochrome P450 (CYP) 1B1 with steroid derivatives

Inhibition of cytochrome P450 1B1 (CYP1B1) represents a promising therapeutic strategy, because it would enable action at three different levels: (1) by inhibiting the formation of mutagenic 4-hydroxy-estradiol, (2) by inhibiting the bioactivation of procarcinogens, and (3) by reducing drug-resistance. Surprisingly, few steroids were reported as inhibitors of CYP1B1. From a screening performed with 90 steroid derivatives, we identified thioestrone (B19) as an inhibitor (IC50=3.4μM) of CYP1B1. Molecular modeling studies showed that the 3-SH group of B19 is closer (3.36Å) to the iron atom of the heme system than the 3-OH group of enzyme substrates estrone and estradiol (4.26Å and 3.58Å, respectively). B19 also produced a better docking GOLD score that correlated with the inhibitory results obtained. The estrane derivative B19 represents an interesting lead compound that can be easily modified to extend the structure–activity relationship study and to provide a next generation of more powerful CYP1B1 inhibitors.

Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (IN CONTROL): a randomised, open-label, crossover trial

Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population. We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903. Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8-67·3) versus 55·4% (53·1-57·7; mean difference 9·6%, 95% CI 8·0-11·2; p<0·0001), with reductions in both time spent in hypoglycaemia (ie, blood glucose ≤3·9 mmol/L [6·8% vs 11·4%, mean difference 4·7%, 3·4-5·9; p<0·0001]) and time spent in hyperglycaemia (ie, blood glucose >10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1-6·9; p<0·0001]). During CGM, the number of severe hypoglycaemic events was lower (14 events vs 34 events, p=0·033). Five serious adverse events other than severe hypoglycaemia occurred during the trial, but all were deemed unrelated to the trial intervention. Additionally, no mild to moderate adverse events were related to the trial intervention. CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population. Eli Lilly and Sanofi.