Molecular modelling, synthesis and in vitro evaluation of quinazolinone hybrid analogues as potential pancreatic lipase inhibitors

Abstract

Obesity 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.

Communicated by Ramaswamy H. Sarma

Keywords:

• Obesity
• pancreatic lipase
• quinazolinone hybrids
• enzyme inhibition
• molecular docking
• molecular dynamics

Acknowledgements

Ginson George acknowledges the fellowship received from the Council for Scientific and Industrial Research (CSIR), New Delhi, India (File No: 09/719(0100)/2019-EMR-I). The authors acknowledge Birla Institute of Technology and Science, Pilani (BITS Pilani), Pilani Campus, Pilani, Rajasthan, India for providing NMR and other necessary laboratory facilities. The authors also acknowledge Department of Science and Technology (DST), New Delhi, India, for sponsoring the HR-MS facility at BITS Pilani under the FIST program.

Disclosure statement

The authors declare no conflicts of interest.