BITS Faculty Publications

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    Computational insights into human UCP1 activators through molecular docking, MM-GBSA, and molecular dynamics simulation studies
    (Elsevier, 2024-12) Paul, Atish Tulshiram
    The prevalence of obesity is rapidly increasing worldwide. Brown adipose tissue activates uncoupling protein 1 (UCP1) to generate heat through bypassing ATP synthesis, offering a potential target for obesity treatment. Targeting UCP1 activation to induce thermogenesis through small molecules presents a promising approach for obesity management. In this study, molecular docking of UCP1 activators, using 2,4-dinitrophenol (DNP) as a reference ligand (PDB ID: 8J1N, docking score: −5.343 kcal/mol), identified seven top-scoring compounds: naringin (-7.284 kcal/mol), quercetin (-6.661 kcal/mol), salsalate (-6.017 kcal/mol), rhein (-5.798 kcal/mol), mirabegron (-5.535 kcal/mol), curcumin (-5.479 kcal/mol), and formoterol (-5.451 kcal/mol). Prime MM-GBSA calculation of the top-scored molecule (i.e., naringin) in the docking study showed ΔGBind of −70.48 kcal/mol. Key interactions of these top 7 activators with UCP1 binding pocket residues Trp280, Arg276, Glu190, Arg83, and Arg91 were observed. Molecular dynamics simulations performed for 100 ns confirmed complex stability, with RMSD values below 6 Å. Additionally, most activators showed favorable intestinal absorption (>90 %) and lipophilicity (LogP 2–4), with pKa values supporting their pharmacological potential as UCP1-targeting therapeutics for obesity. These findings provide a foundation for designing potent UCP1 activators by integrating docking scores, interaction profiles, statistical profiles from MD simulations, and physicochemical assessments to develop effective anti-obesity therapies.
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    Unveiling the potential of naturally occurring rosmarinic acid inspired analogues as pancreatic lipase inhibitors: In silico, in vitro and in vivo evaluation as anti-obesity agents
    (Elsevier, 2025-12) Paul, Atish Tulshiram
    Pancreatic Lipase (PL) is a prime enzyme responsible for the digestion of dietary fat and is considered a safer and more efficient target for managing obesity. Orlistat is the only approved drug for the long-term management of obesity. In this study, using a molecular docking study, various inhibitors were designed via structural optimization of one of the moderately active natural products, namely, rosmarinic acid. A total of 17 acrylate-linked chromone analogues were synthesized, followed by structure elucidation via NMR spectroscopy and HR-MS. To confirm the stereochemistry of the analogues, a single-crystal XRD spectroscopy was performed for analogue 5ab. Among all the synthesized analogues, six analogues were found to exhibit IC50 values in the range of 1.24–2.76 µM. The analogue 5gb was the most potent among the series with IC50 of 1.24 ± 0.296 µM. The enzyme kinetics study revealed a competitive inhibitory mechanism, with Ki values of 0.554 and 0.488 for 5gb and orlistat, respectively. The number of binding sites (n) and binding constant values were obtained through a fluorescence quenching study and found to be 0.57 and 2.97 × 105 L mol−1, respectively, confirming the single binding site of analogue 5gb in the PL enzyme. Through in vivo screening, 5gb was found to exhibit significant weight reduction and normalization of the serum parameters (triglycerides, total cholesterol, HDL, and LDL cholesterol) at a dose of 20 mg/kg. Through a faecal triglyceride quantification study, the PL inhibitory mechanism was confirmed. Further, the histopathological changes (that occurred in obese animals) in liver and adipose tissue were normalized in the case of 5gb treatment groups. Thus, 5gb possessed a comparable anti-obesity activity to that of orlistat.
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    Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, in silico studies and pharmacological investigations
    (Taylor & Francis, 2024-02) Paul, Atish Tulshiram
    A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (16a-e, 17a-d, 18a-c) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a, which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a, wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents.
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    Anti-adipogenic and anti-steatotic potential of edible pigment bixin and annatto seed extracts: LC-MS based bioactive profiling and in vitro biochemical validation
    (Elsevier, 2025-02) Sharma, Pankaj Kumar; Deepa, P.R.
    The rising prevalence of metabolic syndrome (MetS), such as obesity and its hepatic complication, and non-alcoholic fatty liver disease (NAFLD), necessitates safe, effective, and protective interventions. Natural products, such as carotenoids, including bixin derived from annatto seeds, have emerged as promising candidates due to their multifaceted pharmacological properties. This study aimed to characterize the edible food pigment bixin and other co-existing bioactives in acetone- and ethyl lactate-extracts of Bixa Orellana L. seeds, followed by their anti-adipogenic and anti-steatotic assessments using in-vitro models of obesity and NAFLD. LC-MS analysis revealed the presence of various phytochemicals in the bixin rich solvent extracts. In vitro studies demonstrated differential and significant anti-adipogenic and anti-steatotic effects of bixin (pure pigment) and solvent extracts of annatto seeds (P < 0.05). The LC-MS profiling of annatto seed extracts revealed the presence of bixin and several bixinoids. Other key phytochemicals that were identified were eicosatrienoic acid, geranylgeraniol, hypolatein, δ-tocotrienol, caffeoyl acid derivative, and zeaxanthin, which were differentially abundant in each solvent extract. Bixin and coexisting bioactives in the annatto seed extracts demonstrated significant anti-oxidant, anti-inflammatory, and anti-lipidemic effects (P < 0.05) in the present in vitro MetS models. Further studies may be directed toward evaluating the nutraceutical potential of bixin in combination with the implicated phytochemicals in the extracts for treating metabolic disorders.
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    COVID-19 infection and metabolic comorbidities: Mitigating role of nutritional sufficiency and drug – nutraceutical combinations of vitamin D
    (Elsevier, 2023-03) Deepa, P. R.; Tare, Meghana
    The vulnerability of human health is amplified in recent times with global increase in non-communicable diseases (due to lifestyle changes and environmental insults) and infectious diseases (caused by newer pathogens and drug-resistance strains). Clinical management of diseases is further complicated by disease severity caused by other comorbid factors. Drug-based therapy may not be the sole approach, particularly in scenarios like the COVID-19 pandemic, where there is no specific drug against SARS-CoV-2. Nutritional interventions are significant in armouring human populations in disease prevention, and as adjunctive therapy for disease alleviation. Amidst ongoing clinical trials to determine the efficacy of Vit. D against infections and associated complications, this review examines the pleiotropic benefits of nutritional adequacy of vitamin D (Vit. D) in combating viral infections (COVID-19), its severity and complications due to co-morbidities (obesity, diabetes, stroke and Kawasaki disease), based on research findings and clinical studies. Supplements of Vit. D in combination with other nutrients, and drugs, are suggested as promising preventive-health and adjunct-treatment strategies in the clinical management of viral infections with metabolic comorbidities.
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    In silico and in vitro analysis of PPAR – α / γ dual agonists: Comparative evaluation of potential phytochemicals with anti-obesity drug orlistat
    (Elsevier, 2022) Deepa, P.R.; Sharma, Pankaj Kumar; Murugesan, Sankaranarayanan
    Obesity is an abnormal fat accumulation disorder in the metabolic syndrome constellation, and a risk factor for diabetes, cardiovascular disorders, non-alcoholic fatty liver disease (NAFLD), and cancer. Nuclear receptors (Peroxisome proliferator-activated receptor, PPAR) are implicated in metabolic syndrome and NAFLD, and have potential for therapeutic targeting. Nuclear receptors are ligand-dependent transcription factors that have diverse roles in metabolism, including regulating genes involved in lipid and glucose metabolism, modulating inflammatory genes, and are crucial for maintaining metabolic flexibility. PPAR activates adipose triglyceride lipase, which then releases fatty acids as ligands for PPAR, indicating the interdependency of nuclear receptors and lipases. Here, molecular docking was performed with selected phytochemical ligands that can bind with PPAR-α/γ (PDB ID: 2ZNN and 2ATH, respectively) using Glide module of Schrodinger software followed by molecular dynamics simulation study using Desmond module, and ADMET analysis. Interestingly, orlistat which is a well-known lipase and fatty acid synthase inhibitor also demonstrated favorable binding affinity with both PPAR-α/γ (−10.96 kcal/mol against PPARα and −10.26 kcal/mol against PPARγ). The highest docking scores were however shown by the flavonoids - rutin (−14.88 kcal/mol against PPARα and −13.64 kcal/mol against PPARγ), and its aglycone, quercetin (−10.08 kcal/mol in PPARα and −9.89 kcal/mol in PPARγ). The other phytochemicals (genistein, esculin, daidzin, naringenin, daidzein, dihydroxy coumarin, hydroquinone) showed lower binding affinity as dual agonists. The anti-obesity effects were experimentally validated in cultured adipocytes, which revealed better lipid inhibition by rutin and quercetin than orlistat (quercetin > rutin > orlistat) pointing to their strong potential in anti-obesity treatment.
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    Finger millet bran supplementation alleviates obesity-induced oxidative stress, inflammation and gut microbial derangements in high-fat diet-fed mice
    (CUP, 2014-09) Khare, Pragyanshu
    Several epidemiological studies have shown that the consumption of finger millet (FM) alleviates diabetes-related complications. In the present study, the effect of finger millet whole grain (FM-WG) and bran (FM-BR) supplementation was evaluated in high-fat diet-fed LACA mice for 12 weeks. Mice were divided into four groups: control group fed a normal diet (10 % fat as energy); a group fed a high-fat diet; a group fed the same high-fat diet supplemented with FM-BR; a group fed the same high-fat diet supplemented with FM-WG. The inclusion of FM-BR at 10 % (w/w) in a high-fat diet had more beneficial effects than that of FM-WG. FM-BR supplementation prevented body weight gain, improved lipid profile and anti-inflammatory status, alleviated oxidative stress, regulated the expression levels of several obesity-related genes, increased the abundance of beneficial gut bacteria (Lactobacillus, Bifidobacteria and Roseburia) and suppressed the abundance of Enterobacter in caecal contents (P≤ 0·05). In conclusion, FM-BR supplementation could be an effective strategy for preventing high-fat diet-induced changes and developing FM-BR-enriched functional foods.
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    Screening of six Ayurvedic medicinal plants for anti-obesity potential: An investigation on bioactive constituents from Oroxylum indicum (L.) Kurz bark
    (Elsevier, 2017-02) Khare, Pragyanshu
    As an effort to identify newer anti-obesity lead(s) we have selected 13 plant materials from the six plant species which have been reported in Indian Ayurvedic medicine as remedy against complications affecting glucose and lipid homeostasis.
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    Kodo millet whole grain and bran supplementation prevents high-fat diet induced derangements in a lipid profile, inflammatory status and gut bacteria in mice
    (RSC, 2017-01) Khare, Pragyanshu
    The protective role of kodo millet whole grain and bran supplementation in diet induced obesity has not been investigated. Here we have studied the role of kodo millet supplementation in age matched Swiss albino mice that were randomly divided into groups and fed their respective diets for 16 weeks. A high fat diet increased weight gain, reduced glucose tolerance, increased serum lipids, altered hepatic and adipocyte gene expression and caused dysbiosis in the intestinal beneficial bacteria. Kodo millet supplementation did not affect weight gain but it improved glucose tolerance and prevented an increase in the serum cholesterol and lipid parameters (P ≤ 0.05), modulated adipogenesis related gene expression, decreased serum IL-6 and LPS levels (P ≤ 0.05), promoted selected beneficial gut bacterial abundances (Lactobacillus sp., Bifidobacteria, Akkermansia and Roseburia spp.) and improved the total short chain fatty acid production (P ≤ 0.05) and acetate levels (P ≤ 0.05) in cecal contents. This study provides evidence that kodo millet supplementation alleviates high-fat diet induced changes and hence can be incorporated as a functional ingredient for the management of obesity.
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    Dihydrocapsiate supplementation prevented high-fat diet–induced adiposity, hepatic steatosis, glucose intolerance, and gut morphological alterations in mice
    (Elsevier, 2018-03) Khare, Pragyanshu
    Despite the lipolytic and thermogenic properties of capsaicin, its putative use as a weight-lowering dietary supplement has been limited because of the burning sensation caused by capsaicin when it comes in contact with mucous membranes. A potential alternative to capsaicin are the capsinoids, nonpungent capsaicin analogs that exhibit effects similar to capsaicin. Whereas the antiobesity properties of capsinoids have been reported, the effectiveness of FDA-approved synthetic dihydrocapsiate has not yet been investigated. In the present study, we hypothesized that dihydrocapsiate might ameliorate high-fat diet (HFD)–induced metabolic disorders in a manner similar to capsaicin and therefore can be its nonpungent alternative. To test this hypothesis, HFD-fed mice were orally administered dihydrocapsiate (2 and 10 mg/kg body weight) for 12 weeks. Dihydrocapsiate modestly reduced the HFD-induced weight gain and significantly prevented the associated hyperglyceridemia and hyperinsulinemia while improving glucose tolerance. Histological and gene expression analysis showed that dihydrocapsiate significantly prevented the lipid accumulation in white adipose tissue and brown adipose tissue via targeting genes involved in energy expenditure and mitochondrial biogenesis, respectively. Dihydrocapsiate corrected hepatic triglyceride concentrations and normalized expression of genes regulating hepatic lipid and glucose metabolism. Moreover, dihydrocapsiate administration significantly improved gut morphology and altered gut microbial composition, resulting in reduced host energy availability. Collectively, these results indicate that dihydrocapsiate administration improved glucose tolerance, prevented adiposity and hepatic steatosis, as well as improved HFD-induced gut alterations, positing dihydrocapsiate as a potential food ingredient for the dietary management of HFD-induced metabolic alterations.