Recent advances and structure-activity relationship studies of DPP-4 inhibitors as anti-diabetic agents.

Diabetes mellitus (DM) is one of the largest public health problems worldwide and in the last decades various therapeutic targets have been investigated. For the treatment of type-2 DM (T2DM), dipeptidyl peptidase-4 (DPP-4) is one of the well reported target and has established safety in terms of cardiovascular complexicity. Preclinical and clinical studies using DPP-4 inhibitors have demonstrated its safety and effectiveness and have lesser risk of associated hypoglycaemic effect making it suitable for elderly patients. FDA has approved a number of structurally diverse DPP-4 inhibitors for clinical use. The present manuscript aims to focus on the well reported hybrid and non-hybrid analogues and their structural activity relationship (SAR) studies. It aims to provide structural insights for this class of compounds pertaining to favourable applicability of selective DPP-4 inhibitors in the treatment of T2DM.

Optimal Cut-Off Values for Body Mass Index and Fat Mass Index Based on Age in Physically Active Males Using Receiver Operating Characteristic Curve.

This study aims to redefine obesity cut-off points for body mass index (BMI) and fat mass index (FMI) according to the different age groups of physically active males. Healthy physically active volunteers (N = 1442) aged 18-57 years (y), with a mean BMI = 22.7 ± 2.8 kg/m2, and mean FMI = 4.3 ± 1.7 kg/m2 were recruited from various fitness centers. BMI was calculated and individuals were categorized according to the Asia-Pacific BMI criterion of ≤22.9 kg/m2 and the previous WHO-guided BMI criterion of ≤24.9 kg/m2. FMI was also calculated for the study participants with a cut-off of 6.6 kg/m2. Redefining of BMI and FMI cut-off values was carried out based on different age groups categorized with a difference of 10 y and 5 y using the receiver operating characteristic (ROC) curve and Youden's index. For the entire study population, BMI redefined cut-off points for overweight and obesity were 23.7 kg/m2 and 24.5 kg/m2, respectively, while FMI redefined cut-off points for overweight and obesity were 4.6 kg/m2 and 5.7 kg/m2, respectively. With 10 y of age group difference, a constant BMI and FMI values were observed, while with 5 y of age group difference, a constant increase in the BMI cut-offs was observed as the age group increased, i.e., from 23.3 kg/m2 in 20-24 y to 26.6 kg/m2 in ≥45 y and a similar trend was seen in FMI cut-offs. To conclude, our study suggests that age-dependent BMI and FMI cut-off points may provide appropriate measurements for physically active males as the age group increases.

Protein Informatics and Vaccine Development: Cancer Case Study.

Clinical translation is a challenging step in the development of cancer vaccines and is found to be related to the complex nature of cancer immunology. Vaccine-based therapeutic strategies for cancer have gained consideration with the advent of vaccine technology as well as an understanding of cancer immunology. Immunotherapy has been widely used in the treatment of cancer. Some promising candidates have been identified to engineer cancer vaccines like Glycoprotein, Mucin 1, MHC protein, etc. It has benefited from the availability of advanced techniques for rapid identification and selection of proteins for precision engineering. Simultaneously, nanovaccines have been focused on target delivery and artificial intelligence-based approaches for personalized vaccine development. The manuscript summarizes the advances in the development of structurebased cancer vaccines along with the status of clinical studies and applications.

Mutation informatics: SARS-CoV-2 receptor-binding domain of the spike protein.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) undergoes mutations at a high rate and with frequent genetic reassortment (antigenic drift/shift), leading to variability in targets. The receptor-binding domain (RBD) of the spike (S) protein has a major role in the binding of SARS-CoV-2 with human angiotensin-converting enzyme 2 (ACE2). Mutations at the RBD influence the binding interaction at the SARS-CoV-2 S-ACE2 interface and impact viral pathogenicity. Here, we discuss different reported mutations of concern in RBD, physicochemical characteristic changes resulting from mutated amino acids and their effect on binding between the RBD and ACE2. Along with mutation informatics, we highlight recently developed small-molecule inhibitors of RBD and the ACE2 interface. This information provides a rational basis for the design of inhibitors against the multivariant strains of SARS-CoV-2.

Hindi Adaptation and Psychometric Validation of the Affiliate Stigma Scale.

Background: The Affiliate Stigma Scale (ASS) is a widely used tool to measure affiliate stigma in the caregivers of individuals with various types of mental illnesses. However, the Hindi adaptation of this scale with evident psychometric properties is not available. This study aimed to adapt the ASS in the Hindi language and, further, to validate it in the Indian setting. Methods: Translation and back-translation methods were used to translate the original items of the ASS to the Hindi language. After completion of translations and linguistic adaptation process, the Hindi translated version of the ASS, WHO Quality of Life-BREF (WHOQOL-BREF), General Health Questionnaire-12 (GHQ-12), and Hospital Anxiety and Depression Scale (HADS) were administered to 140 caregivers of persons with mental illness. Purposive sampling method was adopted. The age range of the participants was 17-60 years. Psychometric properties, as well as the factor structures of the scale, were evaluated. Results: The Hindi version of the ASS has adequate internal consistencies (r = 0.87-0.93) and test-retest reliability (r = 0.78, P < 0.001). The concurrent validity of this scale was also high, as the correlation coefficients among the Hindi version of the ASS, WHOQOL-BREF, GHQ-12, and HADS were ranging from 0.23 to 0.35. The exploratory factor analysis revealed three underlying factors, namely, cognition, affect, and behavior. Conclusions: The Hindi version of the ASS is a reliable and valid psychometric tool to measure affiliate stigma in caregivers of patients with mental illness.

Non-bonding energy directed designing of HDAC2 inhibitors through molecular dynamics simulation.

Designing an inhibitor having strong affinity in the active site pocket is the cherished goal of structure based drug designing. To achieve this, it is considerably important to predict which structural scaffold is better suited for change to increase affinity. We have explored five HDAC2 co-crystals having PDB ligand code-SHH (vorinostat), LLX, 20Y, IWX (BRD4884) and 6EZ (BRD7232). For analyzing protein-ligand interaction at an atomistic level, we have employed the NAMD molecular dynamics (MD) package. The obtained 100 ns long MD trajectories were subjected to quantitative estimations of non-bonding energies (NBEs) for inferring their interactions with the whole protein or its composite active site (CAS). In addition, relative ΔGbind was calculated to rank the inhibitors. These inhibitors' NBEs reveal that the phenyl moieties are the major structural scaffold where modifications should be attempted. We designed new compounds (NCs) via introducing hydroxyl groups at 4,5 position of the phenyl moiety of 6EZ, called NC1. Improvement in NC1 further encouraged us for CAP modification by isochromane and isoindoline moieties in place of oxabicyclooctane in NC1, resulting in NC2 and NC3. We also explored trifluoromethyl oxadiazole in 6EZ (NC4 and NC5) and SHH (NC6 and NC7). This moiety acts as a ZBG in NC4 while acting as a part of the foot-pocket in the rest. NC2 and NC6 have highest favorable NBEs among all studied ligands due increased favorable electrostatic contribution. We expect these NBEs data will provide atomistic level insights and benefit in designing new and improved HDAC2 inhibitors. Communicated by Ramaswamy H. Sarma.

Prospective mode of action of Ivermectin: SARS-CoV-2.

The well-known anti-helminthic drug ivermectin (IVM) has been established as an example of drug repurposing for the management of SARS-CoV-2 infection. Various study has been done to understand the inhibitory mechanism of IVM against SARS-CoV-2 targets. Broadly, IVM has been categorized as a host-directed agent and the proposed mechanism involves inhibition of the IMPα/ß1-mediated nuclear import of viral proteins. In addition, in vitro/in vivo and molecular docking/dynamic simulation studies suggested multitargets mechanism of IVM against SARS-CoV-2. Present manuscript attempts to provide an overview of the detailed mechanism of action based on experimental and computational studies. The knowledge of binding interaction of IVM and SARS-CoV-2 targets will give the direction to developed new and potential anti-COVID agents.

Chromones: Privileged scaffold in anticancer drug discovery.

In the design and discovery of anticancer drugs, various natural heterocyclic scaffolds have attracted considerable interest as privileged structures. For rational drug design, some of the natural scaffolds such as chromones have exhibited wide acceptability due to their drug-like properties. Among the approved anticancer drugs, the scaffolds with high selectivity for a small group of closely related targets are of importance. In the development of selective anticancer agents, the natural, as well as synthetic, can generate highly selective compounds toward cancer targets. The present manuscript includes more particularly the development of cancer inhibitors incorporating the chromone scaffold, with a strong emphasis on their molecular interactions in the anticancer mechanism. It also includes the structure-activity relationship studies and related examples of lead optimization.

Deciphering Biochemical and Molecular Signatures Associated with Obesity in Context of Metabolic Health.

This study aims to identify the clinical and genetic markers related to the two uncommon nutritional statuses-metabolically unhealthy normal-weight (MUNW) and metabolically healthy overweight/obese (MHOW) individuals in the physically active individuals. Physically active male volunteers (n = 120) were recruited, and plasma samples were analyzed for the clinical parameters. Triglycerides, HDL-Cholesterol, LDL-cholesterol, total cholesterol, C-reactive protein, and insulin resistance were considered as markers of metabolic syndrome. The subjects were classified as 'healthy' (0 metabolic abnormalities) or 'unhealthy' (≥1 metabolic abnormalities) in their respective BMI group with a cut-off at 24.9 kg/m2. Analysis of biochemical variables was done using enzyme linked immunosorbent assay (ELISA) kits with further confirmation using western blot analysis. The microarray was conducted, followed by quantitative real-time PCR to identify and analyze differentially expressed genes (DEGs). The MHOW group constituted 12.6%, while the MUNW group constituted 32.4% of the total study population. Pro-inflammatory markers like interleukin-6, tumor necrosis factor (TNF)-α, and ferritin were increased in metabolically unhealthy groups in comparison to metabolically healthy groups. Gene expression profiling of MUNW and MHOW individuals resulted in differential expression of 7470 and 5864 genes, respectively. The gene ontology (GO) biological pathway analysis showed significant enrichment of the 'JAK/STAT signaling pathway' in MUNW and 'The information-processing pathway at the IFN-ß enhancer' pathway in MHOW. The G6PC3 gene has genetically emerged as a new distinct gene showing its involvement in insulin resistance. Biochemical, as well as genetic analysis, revealed that MUNW and MHOW are the transition state between healthy and obese individuals with simply having fewer metabolic abnormalities. Moreover, it is possible that the state of obesity is a biological adaptation to cope up with the unhealthy parameters.

Effect of endurance training on copper, zinc, iron and magnesium status.

BACKGROUND: Physical activity related energy expenditure, environmental stresses, body composition, dietary intake, etc., are key factors influencing the nutritional requirements of minerals. The present study was designed to study the nutritional status of metals with respect to extensive endurance training. METHODS: The participants of the study were navy sailors (N.=37, mean age±SD: 25.2±4.8 y) undergoing one month of endurance training. Nutritional status was assessed by determining their body composition using bioelectrical impedance (BIA), food intake and urinary excretion levels. Fasting blood samples were taken to separate plasma and red blood cells for analysis of copper, zinc, magnesium and iron and certain metal dependent enzymatic biomarkers. RESULTS: Endurance training significantly decreased the plasma levels of copper (P<0.01), zinc and iron (P<0.05) while in erythrocytes a significant (P<0.001) decrease was observed only for Mg and Zn. There was a concomitant increase (P<0.05) in urinary Zn excretion. In addition, the concentrations of certain metal dependent enzymatic biomarkers like RBC metallothionein (P<0.05) and carbonic anhydrase (P<0.01) (Zn biomarker), plasma ferritin (Fe biomarker) (P<0.001) and RBC Mg ATPase (Mg biomarker) (P<0.05) decreased after physical activity. CONCLUSIONS: The findings of the present study suggested the increased requirements of these minerals during physical activity.

Molecular dynamics study of HDAC8-largazole analogues co-crystals for designing potential anticancer compounds.

The X-ray crystal structures of HDAC8 complexed with largazole thiol (LAR, PubChem CID: 56663191) and its synthetic variants (Ligand ID in PDB, PubChem CID: L6G, 91667418; L7G, 91667421; L8G, 91667420) (PDB codes: 3RQD, 4RN0, 4RN2 and 4RN1) were analyzed using molecular dynamics simulations to comprehend protein-ligand nonbonding energies (NBEs). The NBEs of ligands' substructures vis-à-vis active site indicated that pyridyl fragment (F2B4) in L7G and L8G, and amide fragment (F2B5) in LAR and L6G are in high energy states. Based on ligands' substructures and active site residues properties new compounds were designed by introducing phenolic and amidine moieties, respectively, for F2B4 and F2B5. This improved NBEs of new compounds (NC2, -60.93 kcal/mol; NC3, -42.42 kcal/mol). Also, Zn2+ group (substructure F1) of largazoles was modified with that of SAHA and Trapoxin A. Here, the results indicated in favor of Zn2+ group of Trapoxin A. New compound NC6 incorporating aforesaid modifications i.e. phenolic moiety for F2B4, amidine moiety for F2B5 and Zn2+ group of Trapoxin A in F1, offered best interactions with HDAC8 (-89.75 kcal/mol). Thus, the study revealed new depsipeptides as potential HDAC8 inhibitors. AbbreviationsCAScomposite active siteCHARMMchemistry at Harvard Macromolecular MechanicsCUDAcompute unified device architectureHAThistone acetyletransferaseHDAChistone deacetylaseLARlargazole thiol (or) (2R,5R,8R,11R)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-10-oxa-3,17-dithia-7,14,19,20-tetraazatricyclo[14.2.1.1 ∼ 2,5∼]icosa-1(18),16(19)-diene-6,9,13-trioneL6G(5R, 8S,11S)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-3,17-dithia-7,10,14,19,20-pentaazatricyclo[14.2.1.1 ∼ 2,5∼]icosa-1(18),2(20),16(19)-triene-6,9,13-trione)L7G(5R,8S,11S)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-3-thia-7,10,14,17,21-pentaazatricyclo[14.3.1.1 ∼ 2,5∼]henicosa-1(20),2 (21),16,18-tetraene-6,9,13-trioneL8G(5R,8S,11S)-5-methyl-8-(propan-2-yl)-11-[(1E)-4-sulfanylbut-1-en-1-yl]-3-thia-7,10,14,20,21-pentaazatricyclo[14.3.1.1 ∼ 2,5∼]henicosa-1(20),2(21),16,18-tetraene-6,9,13-trioneMDmolecular dynamicsMOEmolecular operating environmentNAMDnanoscale molecular dynamicsNBEnonbonding energyNBEEelectrostatic nonbonding energyNBEVVan der Waals nonbonding energyNBEFnonbonding energy of fragmentNBEFEelectrostatic nonbonding energy of fragmentNBEFVVan der Waals nonbonding energy of fragmentNCnew compound; Rg: radius of gyration;RMSDroot mean square deviationRMSFroot mean square fluctuationVMDvisual molecular dynamics.Communicated by Ramaswamy H. Sarma.

Effect of physical activity and age on plasma copper, zinc, iron, and magnesium concentration in physically active healthy males.

OBJECTIVES: The concentration of nutritionally important minerals in circulation is under tight homeostatic control, however, physical activity and aging influence their body stores and nutritional requirement. The aim of this study was to evaluate the effect of both physical activity and age on plasma concentrations of copper, zinc, iron, and magnesium. METHODS: Stratified cluster sampling was used for selection of study participants (N = 360) belonging to three physical activity groups: sedentary, moderately active, and highly active on the basis of their physical activity levels as 1.53, 1.8, and 2.3, respectively. They were also divided into six different age groups (18-20, 21-25, 26-30, 31-35, 36-40, and 41-45 y). We assessed nutritional status by determining their body composition using bioelectrical impedance method and measuring intake levels. Fasting blood samples were taken to separate plasma for analysis of copper, zinc, magnesium, and iron. RESULTS: There was a major difference (P < 0.001) in the mean value of plasma copper, zinc, magnesium, and iron for the three activity groups. The plasma copper and iron concentrations were higher in the moderately active group (copper: 1.59 ± 0.05 mg/L, iron: 0.79 ± 0.22 mg/L) whereas zinc concentration was higher in the sedentary group (2.37 ± 0.29 mg/L). Both the highly and moderately active groups had higher plasma magnesium levels compared with the sedentary group. Plasma copper, zinc, magnesium, and iron levels also were influenced by age in a different pattern with respect to physical activity. CONCLUSION: Physical activity-related energy expenditure and age play a remarkable role in deciphering the plasma mineral levels in the healthy individuals.

Raised HIF1α during normoxia in high altitude pulmonary edema susceptible non-mountaineers.

High altitude pulmonary edema (HAPE) susceptibility is associated with EGLN1 polymorphisms, we hypothesized that HAPE-susceptible (HAPE-S, had HAPE episode in past) subjects may exhibit abnormal HIF1α levels in normoxic conditions. We measured HIF1α levels in HAPE-S and HAPE resistant (HAPE-R, no HAPE episode) individuals with similar pulmonary functions. Hemodynamic responses were also measured before and after normobaric hypoxia (Fi02 = 0.12 for 30 min duration at sea level) in both groups. . HIF1α was higher in HAPE-S (320.3 ± 267.5 vs 58.75 ± 33.88 pg/ml, P < 0.05) than HAPE-R, at baseline, despite no significant difference in baseline oxygen saturations (97.7 ± 1.7% and 98.8 ± 0.7). As expected, HAPE-S showed an exaggerated increase in pulmonary artery pressure (27.9 ± 6 vs 19.3 ± 3.7 mm Hg, P < 0.05) and a fall in peripheral oxygen saturation (66.9 ± 11.7 vs 78.7 ± 3.8%, P < 0.05), when exposed to hypoxia. HIF1α levels at baseline could accurately classify members of the two groups (AUC = 0.87). In a subset of the groups where hemoglobin fractions were additionally measured to understand the cause of elevated hypoxic response at baseline, two of four HAPE-S subjects showed reduced HbA. In conclusion, HIF 1 α levels during normoxia may represent an important marker for determination of HAPE susceptibility.

In Silico Exploration for New Antimalarials: Arylsulfonyloxy Acetimidamides as Prospective Agents.

A strategy is described to identify new antimalarial agents to overcome the drug resistance and/or failure issues through in silico screening of multiple biological targets. As a part of this, three enzymes namely CTPS, CK, and GST were selected, from among 56 drug targets of P. falciparum, and used them in virtual screening of ZINC database entries which led to the design and synthesis of arylsulfonyloxy acetimidamides as their consensus inhibitors. From these, two compounds showed good activity against sensitive (3D7; IC50, 1.10 and 1.45 µM) and resistant (K1; IC50, 2.10 and 2.13 µM) strains of the parasite, and they were further investigated through docking and molecular dynamics simulations. The findings of this study collectively paved the way for arylsulfonyloxy acetimidamides as a new class of antimalarial agents.

What is the relevance of contact allergy to sodium metabisulfite and which concentration of the allergen should we use?

BACKGROUND: The prevalence of contact allergy to sodium metabisulfite (SMB) has increased from the range of 1.4% to 1.7% to the range of 3.4% to 6.8% in published series over the past 20 years. AIMS: The aims of this study were to review contact allergy to SMB in our cohort and to investigate different concentrations to define the most appropriate concentration for patch testing. METHODS: Patient records were reviewed between February 2009 and December 2011 to obtain information on patient demographics, clinical presentation, and prevalence of contact allergy to SMB. Patients attending for patch testing, between January 2012 and June 2013, were tested with 3 strengths of SMB as part of the British standard series (1%, 0.1%, and 0.01%). RESULTS: Nine hundred ninety-six patients were patch tested to the British standard series including SMB 1% in petrolatum between February 2009 and June 2013, and 70 (7%) were positive. In the prospective group, 380 were tested to 3 concentrations of SMB (1.0%, 0.1%, and 0.01%). Fourteen patients (3.68%) had a positive patch test with 1% SMB, 7 to 0.1% SMB, and 3 to 0.01% SMB. There was exposure to SMB in 10 patients who cleared with avoidance at review 3 months later. The most frequent location of rash included face, hands, vulval, and perianal region. CONCLUSIONS: Our study confirms reports of increasing prevalence of SMB allergy. A detailed review of exposure in the prospective study showed that SMB is relevant in most patients, and 1% in petrolatum is the best concentration for patch testing.

Synthesis, biological evaluation and molecular modeling studies of new 2,3-diheteroaryl thiazolidin-4-ones as NNRTIs.

In a focused exploration, thiazolidin-4-ones with different C-2 and N-3 substituent groups were synthesized and evaluated as non-nucleoside reverse transcriptase inhibitors against HIV-1. This has led to new active compounds sporting heteroaryls at both C-2 and N-3 positions prompting to view them in the backdrop of nevirapine. To assign the molecular attributes for the activity, the compounds are investigated by docking them into non-nucleoside inhibitor-binding pocket of HIV-1 reverse transcriptase (RT). The most active compounds of this series (7d and 7f) shared spatial features with nevirapine with added molecular flexibility. Furthermore, in molecular dynamics simulations carried out for up to 10 ns, the compounds 7d and 7f showed consistency in their interactions with non-nucleoside inhibitor-binding pocket of HIV-1 RT and suggested Tyr319 and Val106 as potential residues for H-bond interaction with these molecules. These results open new avenues for the exploration of 2,3-diheteroaryl thiazolidin-4-ones for prevention of HIV-1.

Target based drug design - a reality in virtual sphere.

The target based drug design approaches are a series of computational procedures, including visualization tools, to support the decision systems of drug design/discovery process. In the essence of biological targets shaping the potential lead/drug molecules, this review presents a comprehensive position of different components of target based drug design which include target identification, protein modeling, molecular dynamics simulations, binding/catalytic sites identification, docking, virtual screening, fragment based strategies, substructure treatment of targets in tackling drug resistance, in silico ADMET, structural vaccinology, etc along with the key issues involved therein and some well investigated case studies. The concepts and working of these procedures are critically discussed to arouse interest and to advance the drug research.

Synthesis of 2,3,6-trideoxy sugar triazole hybrids as potential new broad spectrum antimicrobial agents.

Here, we describe a molecular hybridization inspired design and synthesis of novel 6-triazolyl 2,3,6-trideoxy sugars as promising new broad-spectrum antimicrobial agents using click chemistry in key step. These compounds showed MIC between 0.39 and 50 µg/mL against different native and resistant bacteria and fungi with no toxicity. Among them, compound 29 was the most active molecule with MIC 0.78 µg/mL against Staphylococcus aureus and Klebsiella pneumoniae and 3.12 µg/mL against methicillin- and vancomycin-resistant S. aureus. Compound 26 was the most potent anti-fungal candidate with MIC 0.39 µg/mL against Trichophyton mentagrophytes. Compound 46 was found to be promising with broad-spectrum activity against both bacterial and fungal strains. The bioinformatic studies involving bacteria's protein co-crystals prompted penicillin binding protein-2 as the most likely target of these compounds.

Alterations in different indices of skeletal health after prolonged residency at high altitude.

AIMS: The aim of this study was to evaluate the effect of prolonged residency at high altitude (HA) on different indices of bone health in sea level (SL) residents staying at an altitude of 3450 m for 4 months to 1 year. The assessment of bone health parameters included multisite quantitative bone speed of sound (SOS), and markers of bone metabolism such as serum alkaline phosphatase (ALP), bone specific alkaline phosphatase (BAP), urinary deoxypyridinoline (DPD), C-terminal propeptide of type I collagen (CICP), N-telopeptide of type I collagen (NTX), and hormonal regulators such as 25-hydroxy vitamin D3 (25Vit D), intact parathyroid hormone (i-PTH), and cortisol. RESULTS: The body weight in all the age groups was significantly lower at HA as compared to SL values. Prolonged residency at HA led to a significant decline in bone strength in terms of SOS, both at radius and phalanx. There was a significant increase in circulating Ca and ALP levels. Serum i-PTH and 25VitD levels decreased significantly. Significant decreases were also observed in CICP and BAP, bone formation markers, and serum NTX, DPD/Cr ratio, markers of bone resorption. CONCLUSION: These observations suggest that prolonged residency under hypoxic environment is associated with a decline in both bone formation and bone resorption markers, reflecting a lower bone turnover at HA.