Synthetic pancreatic lipase inhibitors in obesity treatment: current updates on in silico design, synthesis, bioactivity, and SAR

Abstract

Taking a stand against obesity is an urgent priority, as it significantly impacts both the global economy and public health. Synthetic pancreatic lipase (PL) inhibitors represent one of the most effective therapeutics in the management of obesity. PL is a triacylglycerol acyl hydrolase from the family of serine hydrolases that play a key role in the hydrolysis of dietary fat into monoglycerides and fatty acids. Further, fatty acids get deposited in adipose tissue, which progressively results in weight gain. Over the last decade, various new drugs have been studied; however, orlistat still remains the first-line FDA-approved drug for obesity management. However, long-term use of orlistat can lead to serious health complications, including liver toxicity, osteoporosis, and gastrointestinal issues. Notably, the formation of an irreversible covalent bond of the β-lactone moiety of orlistat with the active serine site of HPL and PPL enzyme has been considered to be responsible for these complications. A deeper understanding of the crystal structure of HPL indicates that repositioning the hydrophobic lid domain, also known as the flap, opens access for designed inhibitors to interact with the active site residues: Ser152, His263, and Asp176. Additionally, predicting the mode of inhibition and the inhibition constant (Ki) value through enzyme kinetic study is helpful. This review presents a comprehensive overview of the in silico design, synthetic strategies, in vitro assays using human (HPL) and porcine (PPL) enzymes, in vivo activity, and structure–activity relationship (SAR) studies of synthetic PL inhibitors reported since 2014, aimed at the development of anti-obesity agents. Additionally, we propose the challenges to overcome and a potential path for future development in this field.