High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors.
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.


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.


CONCLUSIONS
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.
Department of Biotechnology, K L University, Guntur, India.
Ganesh Kumar
GK
Veeramachaneni
Department of Biotechnology, K L University, Guntur, India.
K Kranthi
KK
Raj
Department of Biotechnology, K L University, Guntur, India.
Leela Madhuri
LM
Chalasani
Department of Biotechnology, K L University, Guntur, India.
Jayakumar Singh
JS
Bondili
Department of Biotechnology, K L University, Guntur, India.
Venkateswara Rao
VR
Talluri
D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D062126:Databases, Chemical; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008024:Ligands; D008049:Lipase / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology
D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D008049:Lipase
ZINC database; docking; extra precision; molecular dynamic simulations; obesity; triglycerides