Department of Pharmacy
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Item Computational insights into human UCP1 activators through molecular docking, MM-GBSA, and molecular dynamics simulation studies(Elsevier, 2024-12) Paul, Atish TulshiramThe 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.Item 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 TulshiramPancreatic 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.Item Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, in silico studies and pharmacological investigations(Taylor & Francis, 2024-02) Paul, Atish TulshiramA 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.Item Design and Synthesis of Echitamine-inspired Hybrid Analogues Containing Thiazolidinediones as Potential Pancreatic Lipase Inhibitors(Bentham Science, 2022-11) Paul, Atish TulshiramObesity is a multifactorial metabolic disease characterised by excessive accumulation of triglycerides. The prevalence and morbidity rates associated with obesity are increasing tremendously, posing a significant risk to society. Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered an attractive target in obesity.Item Synthesis, molecular modelling and pharmacological evaluation of novel indole-thiazolidinedione based hybrid analogues as potential pancreatic lipase inhibitors(Taylor & Francis, 2023-12) Paul, Atish TulshiramA series of novel indole-thiazolidinedione hybrid analogues (7a to 7 u) were synthesised, characterised and evaluated for their potential Pancreatic Lipase (PL) inhibition. Amongst the screened analogues, 7r was found to be the most active PL inhibitor with an IC50 of 2.67 µM. Furthermore, enzyme inhibition kinetics study revealed a competitive mode of inhibition by the analogues. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking was performed using human PL (PDB ID: 1LPB) and were in agreement with the in vitro results (Pearson’s r = 0.8355, p < 0.05). A molecular dynamics study (100 ns) indicated that 7r was stable in a dynamic environment. The analogue 7r exhibited potential antioxidant activity and was devoid of cytotoxic effect on RAW 264.7 cells. Based on the in-vitro profiles, 7r was selected for the in-vivo pharmacological evaluation. Oral triglyceride tolerance test highlighted effect of 7r on the inhibition of triglyceride absorption. A four-week treatment of 7r in the HFD feed mice provided information regarding its anti-obesity effect with respect to parameters such as body weight, triglycerides, total cholesterol and high-density lipids. Quantification of the faecal triglyceride contents inveterates the potential role of 7r in the PL inhibition. Overall, the synthesized analogue 7r exerted an anti-obesity effect comparable to orlistat. All these results demonstrated the potential role of the newly synthesised indole-thiazolidinedione hybrid analogues in PL inhibition and may be studied further to find potential drug candidates for treating obesity.Item Pancreatic lipase and its related proteins: where are we now?(Elsevier, 2024-01) Paul, Atish TulshiramObesity is a disease of epidemic proportions, with a worrisome upward trend. The high consumption of lipids, a major energy source, leads to obesity because of their high calorific value. Pancreatic lipase (PTL), produced by pancreatic acinar cells, hydrolyzes 50–70% of triacylglycerol (TAG) from food. PTL-related protein 1 (PLRP1) and 2 (PLRP2) are also produced by these cells. In vertebrates, PLRP1 has relatively less lipolytic activity, whereas PLRP2 has an essential role in lipid digestion, especially in infants. In this review, we summarize the structure and function of PTL, PLRP1, and PLRP2, and the metabolic fate of PTL inhibitors. We also discuss the current status of clinical trials on orlistat and its combinations for obesity treatment.Item Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide-Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors(Wiley, 2023-08) Paul, Atish TulshiramInhibition of Pancreatic lipase (PL) is considered to be a promising target for the management of obesity, owing to its crucial role in the digestion of dietary triglycerides. A series of 31 indolyl ketohydrazide-hydrazone analogs (5 aa–cm) were designed, synthesized and evaluated for their PL inhibitory potential. The analogs were designed using molecular modelling studies. The designed analogs were then synthesized by condensation of indolyl oxoacetohydrazide with various substituted benzaldehydes. All the synthesized analogs showed PL inhibitory activity in the range of 4.13–48.35 μM, as compared with orlistat (0.86±0.09 μM). The most potent analog 5 bi (IC50=4.13±0.95 μM) was found to show a competitive type of inhibition with Ki value of 0.725 μM. Additionally, the molecular docking study proved the binding of analog 5 bi at the active site of PL (PDB ID: 1LPB) with MolDock score of −141.279 kcal/mol. It also exhibited various interactions with the key amino acids namely Phe77, Phe215, Tyr114, Ser152, Arg256, His263, etc. Furthermore, the protein-ligand complex of analog 5 bi was found to be stable in molecular dynamics simulation for 100 ns with RMSD of less than 3.2 and 4 Å for the protein and ligand, respectively. The current work hereby provides a basis for the potential role of indolyl ketohydrazide-hydrazone analogs in PL inhibition and further optimization could result in the generation of new leads as anti-obesity agents.Item Synthesis of amide warhead containing coumarin derivatives as potential pancreatic lipase inhibitors: in silico and in vitro evaluation for obesity treatment(Springer, 2023-07) Paul, Atish TulshiramA series of coumarin-3-carboxamide analogues has been designed, synthesized and assessed for their ability to inhibit pancreatic lipase (PL). Amongst all the synthesized analogues 5q, 5k and 5c exhibited potential PL inhibition activity with IC50 values of 19.41, 21.30 and 24.90 µM, respectively when compared to orlistat (IC50 = 0.97 µM). Analogue 5q was found to inhibit PL with IC50 value of 19.41 µM and in a competitive manner with an inhibition constant (Ki) of 10.386 µM. Further, the docking study confirmed the interaction of analogue 5q (MolDock score of −113.845 kcal mol−1) with important active site amino acids, namely Phe 77, Arg 256, His 263, etc. The MolDock scores displayed a substantial association with their inhibitory activity (Pearson’s r = 0.5139), which was consistent with the in vitro results for these analogues. In order to comprehend the stability of the protein-ligand complex (5q) in a dynamic environment, a molecular dynamics study (100 ns) was conducted, and the findings indicated that this complex was stable under dynamic conditions. Overall, our findings demonstrated that the synthesized coumarin-3-carboxamide analogues had the ability to inhibit PL.Item Impact of quercetin on pharmacokinetics of quetiapine: insights from in-vivo studies in wistar rats(Taylor & Francis, 2020-07) Paul, Atish TulshiramQuercetin (QCN) is commonly used in high doses as a dietary supplement for weight loss. Psychotic patients are at greater risk of developing obesity than the general population. The present study was designed to understand the impact of QCN on the exposure of quetiapine (QTE), an anti-psychotic drug with narrow therapeutic index and brain penetrating capability. The content of QTE in rat plasma was analyzed through liquid chromatography–tandem mass spectrometry. The results showed a significant (p < 0.05) increase in exposure of QTE (peroral dosed) in the animals pre-treated with QCN as compared to the control group. All the animals pre-treated with QCN, succumbed to death within 3–5 min of intravenous dosing of QTE (1 mg/kg). The studies in rat liver S9 fraction indicated that QCN could increase the metabolic stability of QTE by inhibiting the activity of CYP enzymes. The brain to plasma ratio of QTE increased upon QCN pre-treatment (2.6 vs 7.7), which could be attributed to P-glycoprotein inhibition at the blood–brain barrier by QCN. The current set of studies indicated that serious herb–drug interaction between QCN and QTE might occur when they are co-administered. Caution is advised for concomitant use of QCN rich dietary supplements with QTE.Item Molecular modelling, synthesis and in vitro evaluation of quinazolinone hybrid analogues as potential pancreatic lipase inhibitors(Taylor & Francis, 2022-11) Paul, Atish TulshiramObesity is a multifactorial metabolic disorder, growing in an alarming rate across the world. Amongst the numerous targets explored for obesity management, inhibition of pancreatic lipase (PL) is considered as one of the promising approaches. Orlistat is the only PL inhibitory drug approved for long term treatment of obesity. However, it is reported to possess hepatotoxicity and nephrotoxicity. Thus, novel drug candidates that act through PL inhibition are considered the hour’s need. Based on this aim, a series of quinazolinone hybrid analogues have been synthesized, characterized and evaluated for their PL inhibitory potential. The physicochemical properties and toxicity parameters suggested that these parameters are in an acceptable range for the screened analogues. Amongst the synthesised analogues, QH-25 exerted potential PL inhibition (IC50 = 16.99 ± 0.54 µM). Further, enzyme inhibition studies suggested a reversible competitive inhibition. Molecular docking of these analogues was in line with in vitro results, wherein the obtained MolDock scores exhibited a significant correlation with their inhibitory activity (Pearson’s r = 0.6629). To further confirm the stability of the QH-25-PL complex in a dynamic environment, a molecular dynamics study (100 ns) was carried out and the results suggested that this complex is stable at dynamic conditions. Overall, these results shed light on the quinazolinone hybrids as potential PL inhibitors. Further structural modification may result in the development of potent anti-obesity agents which acts through PL inhibition.