Biaryl carboxamide-based peptidomimetics analogs as potential pancreatic lipase inhibitors for treating obesity.

A series of 1,1'-biphenyl-3-carboxamide and furan-phenyl-carboxamide analogs were synthesized using an optimized scheme and confirmed by 1H and 13C nuclear magnetic resonance and high-resolution mass spectrometry techniques. The synthesized peptidomimetics analogs were screened in vitro to understand the inhibitory potential of pancreatic lipase (PL). Analogs were assessed for the PL inhibitory activity based on interactions, geometric complementarity, and docking score. Among the synthesized analogs, 9, 29, and 24 were found to have the most potent PL inhibitory activity with IC50 values of 3.87, 4.95, and 5.34 µM, respectively, compared to that of the standard drug, that is, orlistat, which inhibits PL with an IC50 value of 0.99 µM. The most potent analog, 9, exhibited a competitive-type inhibition with an inhibition constant (Ki) of 2.72 µM. In silico molecular docking of analog 9 with the PL (PDB ID:1LPB) showed a docking score of -11.00 kcal/mol. Analog 9 formed crucial hydrogen bond interaction with Ser152, His263, π-cation interaction with Asp79, Arg256, and π-π stacking with Phe77, Tyr114 at the protein's active site. The molecular dynamic simulation confirmed that analog 9 forms stable interactions with PL at the end of 200 ns with root mean square deviation values of 2.5 and 6 Å. No toxicity was observed for analog 9 (concentration range of 1-20 µM) when tested by MTT assay in RAW 264.7 cells.

UCP1 activation: Hottest target in the thermogenesis pathway to treat obesity using molecules of synthetic and natural origin.

Uncoupling protein 1 (UCP1) has been discovered as a possible target for obesity treatment because of its widespread distribution in the inner mitochondrial membrane of brown adipose tissue (BAT) and high energy expenditure capabilities to burn calories as heat. UCP1 is dormant and does not produce heat without activation as it is inhibited by purine nucleotides. However, activation of UCP1 via either direct interaction with the UCP1 protein, an increase in the expression of UCP1 genes or the physiological production of fatty acids can lead to a rise in the thermogenesis phenomenon. Hence, activation of UCP1 through small molecules of synthetic and natural origin can be considered as a promising strategy to mitigate obesity.