High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors
Authors Veeramachaneni GK, Raj KR, Chalasani LM, Bondili JS, Talluri VR
Received 5 March 2015
Accepted for publication 30 April 2015
Published 6 August 2015 Volume 2015:9 Pages 4397—4412
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Professor Shu-Feng Zhou
Ganesh Kumar Veeramachaneni, K Kranthi Raj, Leela Madhuri Chalasani, Jayakumar Singh Bondili, Venkateswara Rao Talluri
Department of Biotechnology, K L University, Guntur, India
Background: Obesity is a progressive metabolic disorder in the current world population, and is characterized by the excess deposition of fat in the adipose tissue. Pancreatic lipase is one of the key enzymes in the hydrolysis of triglycerides into monoglycerides and free fatty acids, and is thus considered a promising target for the treatment of obesity. The present drugs used for treating obesity do not give satisfactory results, and on prolonged usage result in severe side effects. In view of the drastic increase in the obese population day-to-day, there is a greater need to discover new drugs with lesser side effects.
Materials and methods: High-throughput virtual screening combined with e-pharmacophore screening and ADME (absorption, distribution, metabolism, and excretion) and PAINS (pan-assay interference compounds) filters were applied to screen out the ligand molecules from the ZINC natural molecule database. The screened molecules were subjected to Glide XP docking to study the molecular interactions broadly. Further, molecular dynamic simulations were used to validate the stability of the enzyme–ligand complexes. Finally, the molecules with better results were optimized for in vitro testing.
Results: The screening protocols identified eight hits from the natural molecule database, which were further filtered through pharmacological filters. The final four hits were subjected to extra precision docking, and the complexes were finally studied with molecular dynamic simulations. The results pointed to the zinc 85893731 molecule as the most stable in the binding pocket, producing consistent H-bond interaction with Ser152 (G=-7.18). The optimized lead molecule exhibited good docking score, better fit, and improved ADME profile.
Conclusion: The present study specifies zinc 85893731 as a lead molecule with higher binding score and energetically stable complex with pancreatic lipase. This lead molecule, along with its various analogs, can be further tested as a novel inhibitor against pancreatic lipase using in vitro protocols.
Keywords: obesity, triglycerides, ZINC database, docking, extra precision, molecular dynamic simulations
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