Design, synthesis, biological evaluation and molecular modelling studies of oxoacetamide warhead containing indole-quinazolinone based novel hybrid analogues as potential pancreatic lipase inhibitors

Auti, Prashant S.; Nandi, Arijit; Kumari, Vijeta; Paul, Atish T.

doi:10.1039/d2nj01210c

Cited by 16 publications

(16 citation statements)

References 32 publications

(40 reference statements)

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“…Similarly, Auti et al also synthesized a novel series of indole-quinazolinone based hybrid analogs containing α-ketoamide fragment, that resulted in an analog with potent PL inhibitory activity (IC 50 = 4.86 � 0.46 μM). [5] Such results confirms the role of α-ketoamide fragment in the interaction with Ser152 amino acid, present at the active site of PL. Recently "Molecular Hybridization" approach has gained much importance in the process of drug discovery, that involves combining 2 or more pharmacologically active fragments or heterocycles in the same drug molecule.…”

Section: Introductionsupporting

confidence: 70%

“…As far as pharmacotherapy is concerned, the inhibition of fat metabolizing enzymes, that aid in the digestion and absorption of fats are considered promising, mainly due to their local action. [5] Lipases, also called triacylglycerol hydro-lases, are involved in the digestion of triglycerides and phospholipids. [6] Amongst these, inhibition of Pancreatic Lipase (PL) has been validated as a promising target, owing to its crucial role in dietary fat digestion (50-70 %).…”

Section: Introductionmentioning

confidence: 99%

“…This strained lactone ring in the scaffold was discovered to form a covalent bond with Ser152 amino acid (catalytic amino acid residue). [5] Various fragments such as ketoamide, acrylate, βlactone etc. that can interact with serine have been explored and reported for PL inhibition.…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide‐Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors

Jagetiya,

Auti,

Paul

2023

Chemistry & Biodiversity

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Inhibition of Pancreatic lipase (PL) is considered to be a promising target for management of obesity, owing to its crucial role in the digestion of dietary triglycerides. A series of 31 indolyl ketohydrazide‐hydrazone analogues (5aa‐cm) were designed, synthesized and evaluated for their PL inhibitory potential. The designed analogues were synthesized by condensation of indolyl oxoacetohydrazide with various substituted benzaldehydes. All the analogues 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 analogue 5bi (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 analogue 5bi at the active site of PL (PDB ID: 1LPB) with MolDock score of ‐141.279 kcal/mol. Furthermore, the protein‐ligand complex of analogue 5bi 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 analogues in PL inhibition and further optimization could result in the generation of new leads as anti‐obesity agents.

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Section: Introductionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide‐Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors

Jagetiya,

Auti,

Paul

2023

Chemistry & Biodiversity

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“…The Prime-refined receptor–ligand complexes within 30 kcal/mol were then redocked using the Glide XP mode. The default settings for other parameters were maintained [ 27 ].…”

Section: Methodsmentioning

confidence: 99%

The Abundant Phytocannabinoids in Rheumatoid Arthritis: Therapeutic Targets and Molecular Processes Identified Using Integrated Bioinformatics and Network Pharmacology

Nandi¹,

Das

Dey³

et al. 2023

Life

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The endocannabinoid system consists of several phytocannabinoids, cannabinoid receptors, and enzymes that aid in numerous steps necessary to manifest any pharmacological activity. It is well known that the endocannabinoid system inhibits the pathogenesis of the inflammatory and autoimmune disease rheumatoid arthritis (RA). To the best of our knowledge, no research has been done that explains the network-pharmacology-based anti-rheumatic processes by focusing on the endocannabinoid system. Therefore, the purpose of this study is to further our understanding of the signaling pathways, associated proteins, and genes underlying RA based on the abundant natural endocannabinoids. The knowledge on how the phytocannabinoids in Cannabis sativa affect the endocannabinoid system was gathered from the literature. SwissTarget prediction and BindingDB databases were used to anticipate the targets for the phytocannabinoids. The genes related to RA were retrieved from the DisGeNET and GeneCards databases. Protein–protein interactions (high confidence > 0.7) were carried out with the aid of the string web server and displayed using Cytoscape. The Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway analysis was used to perform enrichment analyses on the endocannabinoid–RA common targets. ShinyGO 0.76 was used to predict the biological processes listed in the Gene Ontology (GO) classification system. The binding affinity between the ligand and the receptors was precisely understood using molecular docking, induced-fit docking, and a molecular dynamics simulation. The network pharmacology analyses predicted that processes like response to oxygen-containing compounds and peptodyl-amino acid modification are related to the potential mechanisms of treatment for RA. These biological actions are coordinated by cancer, neuroactive ligand–receptor interaction, lipids and atherosclerosis, the calcium signaling pathway, and the Rap1 signaling pathway. According to the results of molecular docking, in the context of RA, phytocannabinoids may bind to important target proteins such PIK3CA, AKT1, MAPK9, PRKCD, BRAF, IGF1R, and NOS3. This entire study predicted the phytocannabinoids’ systemic biological characteristics. Future experimental research is needed, however, to confirm the results so far.

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“…The constant-temperature, constant-pressure ensemble (NPT) was used for the MD simulation at a temperature of 310 K and an atmospheric pressure of 1.013 bar for 50 ns. The output of the molecular dynamics studies was studied in detail using the Simulation Interactions Diagram Report of the Desmond software (Bowers et al, 2006;Auti et al, 2022).…”

Section: Molecular Dynamicsmentioning

confidence: 99%

Inhibitory activity of Enhydra fluctuans Lour. on calcium oxalate crystallisation through in silico and in vitro studies

Chattaraj¹,

Nandi²,

Das

et al. 2023

Front. Pharmacol.

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The decoction of the whole plant of Enhydra fluctuans is used ethno medicinally by various tribes for the treatment of kidney stones and urinary problems. However, no scientific studies were carried out to delineate its influence on urinary stone formation and crystallisation. Hence, the present study is proposed to investigate the effect of the aqueous extract of Enhydra fluctuans extract on in vitro crystallisation of calcium oxalate. The present study also evaluated. in silico studies of the metabolites with the target proteins present in the renal calcium oxalate stone matrix. The plant material was subjected to decoction to obtain an aqueous extract. The effect of the extract on calcium oxalate crystallization was evaluated by in vitro nucleation and aggregation assays. Further, the metabolites present in E. fluctuans were mined from the existing literature and their number was found to be 35. The selected 35 metabolites of E. fluctuans were subjected to molecular docking with the 5 proteins which are known to be responsible for calcium oxalate crystal growth. Results of in vitro studies indicated that the extract (50, 100, and 200 μg/mL) and standard drug cystone (1,000 μg/mL) exhibited an inhibitory role in the nucleation process where the percentage inhibitions were 52.69, 43.47, 21.98, and 31.67 μg/mL respectively. The results of molecular docking studies revealed that 2 out of 35 metabolites i.e. Baicalein-7-O-diglucoside and 4′,5,6,7-Tetrahydroxy-8-methoxy isoflavone-7-O-beta-D- galactopyranosyl-(1→3)-O-beta-D-xylopyranosyl-(1→4)- O-alpha-L-rhamnopyranoside showed modulatory effects on the four renal stone matrix-associated protein (Human CTP: Phosphoethanolamine Cytidylyltransferase (Protein Data Bank ID: 3ELB), UDP glucose: glycoprotein glucosyltransferase 2 (Gene: UGGT2) (AlphaFold) and RIMS-binding protein 3A (Gene: RIMBP3) (AlphaFold), and Ras GTPase activating-like protein (PDB: 3FAY) based on their docking scores which indicates that they may inhibit the crystallization process. Findings from this study show that Enhydra fluctuans may be effective in the prevention of the crystallization of calcium oxalate. However, further, in vivo studies as well as molecular studies are needed to be conducted to confirm and strengthen its anti-urolithiatic activity and to elucidate the possible mechanism of action involved therein.

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Design, synthesis, biological evaluation and molecular modelling studies of oxoacetamide warhead containing indole-quinazolinone based novel hybrid analogues as potential pancreatic lipase inhibitors

Abstract: A novel series of indolyl oxoacetamide-quinazolinone hybrid analogues (9aa-9df) were designed, synthesized, and evaluated for their in vitro Pancreatic Lipase (PL) inhibitory potential that may lead to efficient anti-obesity agents....

Cited by 16 publications

References 32 publications

Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide‐Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors

Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide‐Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors

The Abundant Phytocannabinoids in Rheumatoid Arthritis: Therapeutic Targets and Molecular Processes Identified Using Integrated Bioinformatics and Network Pharmacology

Inhibitory activity of Enhydra fluctuans Lour. on calcium oxalate crystallisation through in silico and in vitro studies

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