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High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors.
Drug Des Devel Ther. 2015; 9:4397-412.DD

Abstract

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.

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Authors+Show Affiliations

Veeramachaneni GK

Department of Biotechnology, K L University, Guntur, India.

Department of Biotechnology, K L University, Guntur, India.

Department of Biotechnology, K L University, Guntur, India.

Department of Biotechnology, K L University, Guntur, India.

Department of Biotechnology, K L University, Guntur, India.

MeSH

Anti-Obesity AgentsDatabases, ChemicalDrug DesignEnzyme InhibitorsHigh-Throughput Screening AssaysHumansLigandsLipaseMolecular Docking SimulationMolecular Dynamics SimulationObesity

Pub Type(s)

Journal Article

Validation Study

Language

eng

PubMed ID

26273199

Citation

Veeramachaneni, Ganesh Kumar, et al. "High-throughput Virtual Screening With E-pharmacophore and Molecular Simulations Study in the Designing of Pancreatic Lipase Inhibitors." Drug Design, Development and Therapy, vol. 9, 2015, pp. 4397-412.

Veeramachaneni GK, Raj KK, Chalasani LM, et al. High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors. Drug Des Devel Ther. 2015;9:4397-412.

Veeramachaneni, G. K., Raj, K. K., Chalasani, L. M., Bondili, J. S., & Talluri, V. R. (2015). High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors. Drug Design, Development and Therapy, 9, 4397-412. https://doi.org/10.2147/DDDT.S84052

Veeramachaneni GK, et al. High-throughput Virtual Screening With E-pharmacophore and Molecular Simulations Study in the Designing of Pancreatic Lipase Inhibitors. Drug Des Devel Ther. 2015;9:4397-412. PubMed PMID: 26273199.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - High-throughput virtual screening with e-pharmacophore and molecular simulations study in the designing of pancreatic lipase inhibitors. AU - Veeramachaneni,Ganesh Kumar, AU - Raj,K Kranthi, AU - Chalasani,Leela Madhuri, AU - Bondili,Jayakumar Singh, AU - Talluri,Venkateswara Rao, Y1 - 2015/08/06/ PY - 2015/8/15/entrez PY - 2015/8/15/pubmed PY - 2016/4/19/medline KW - ZINC database KW - docking KW - extra precision KW - molecular dynamic simulations KW - obesity KW - triglycerides SP - 4397 EP - 412 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 9 N2 - 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. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/26273199/High_throughput_virtual_screening_with_e_pharmacophore_and_molecular_simulations_study_in_the_designing_of_pancreatic_lipase_inhibitors_ DB - PRIME DP - Unbound Medicine ER -