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Item Discovery of novel chromone and acrylate-based pancreatic lipase inhibitors: Molecular modelling, synthesis, and in vitro evaluation for the treatment of obesity(Wiley, 2024-01) Paul, Atish TulshiramBy the optimization of previously established pancreatic lipase (PL) inhibitory lead, we have developed novel chromone-containing analogues with embedded acrylate fragment as potential PL inhibitors. The analogues were designed by considering the structural features required for binding at the active site of PL enzyme with the utilization of molecular docking study. An optimized synthetic scheme was utilized for the synthesis of designed analogues of prototypes 1&2. Through in vitro PL inhibitory screening, three analogues namely, 5fj, 5gj and 9a were identified as potent PL inhibitory leads with IC50 values of 4.92, 4.23 and 3.32 μM, respectively. The protein binding of analogue 9a was analysed by fluorescence quenching study and it was found to bind at one binding site with a binding constant of 1.93 × 105 L mol−1. Analogue 9a also exhibited a competitive inhibitory mechanism with Ki value of 1.601 μM. In future, the potent lead 9a can be optimized to get a comparable or more potential PL inhibitory activity than marketed drugs.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 Synthesis, molecular modelling and biological evaluation of novel benzyloxy substituted indolyl oxoacetamides as potent pancreatic lipase inhibitors(Springer, 2025-08) Paul, Atish TulshiramA series of 21 indolyl oxoacetamide analogues with benzyloxy-substituents were designed, synthesized and characterized using 1H NMR (Nuclear Magnetic Resonance), 13C NMR, and HRMS (High Resolution Mass Spectrometry) analysis. All the analogues were tested for inhibitory activity against pancreatic lipase. Two analogues, 9f and 10f, exhibited significant activity (IC50 of 2.89 and 2.50 µM, respectively), comparable to the standard drug, orlistat (IC50 = 0.99 µM). The potent analogues 10f and 9f exhibited significant binding affinity for pancreatic lipase (-170.222 kcal mol− 1 and − 153.547 kcal mol− 1). Additionally, both the potent analogues exhibited crucial interaction with Ser 152 and His 263 residues in the PL active site via hydrogen bonding. Molecular dynamics (MD) simulation was performed on the ligand-receptor complex of potent analogue (10f) for 200 ns. The molecule was stabilized by extending the π-π interactions with Phe 77 and Phe 215 of the active site lid domain due to benzyloxy substitution. Toxicity profile prediction indicated that all the analogues were non-hepatotoxic, unlike orlistat.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 Chromone-3-acrylic acid ester analogues: Design, synthesis and biological evaluation as potential pancreatic lipase inhibitors(Elsevier, 2023-12) Paul, Atish TulshiramA novel series of 21 chromone-3-acrylic acid ester analogues (5aa-5cm) were designed, synthesized and evaluated for PL inhibitory activity. The molecular docking study indicate that all the designed chromone analogues have the good binding ability (MolDock score: -115.86 to -160.07 kcal/mol) in the active site of PL enzyme (PDB ID: 1LPB), showing interactions with essential amino acid residues (Phe77, Tyr114, Ser152, Phe215, Arg256). Also, all the analogues were checked for in silico drug likeness property and all were found to have drug like properties, obeying Lipinski rule of 5, with no PAINS alerts. Analogue 5am, with the best docking score, was stable in molecular dynamics simulation for 100 ns (maximum RMSD of 6.4 Å), showing crucial amino acid interactions for more than 60% of the simulation time. The structure of the synthesized analogues were then confirmed by NMR, HRMS and IR spectroscopy. Among the synthesized analogues, 5am and 5ad exhibited potent PL inhibition with IC50 of 5.16 ± 0.287 & 5.82 ± 0.933 µM, respectively, as compared with orlistat (IC50 = 0.86 ± 0.09 µM). The inhibition kinetics and in silico studies confirmed competitive type of inhibition of analogue 5am. The current work highlights the importance of chromone analogues as potential PL inhibitors. Further, the lead optimization may lead to much more potential PL inhibitors.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.