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

Veeramachaneni GK, Raj KK, Chalasani LM, Bondili JS, Talluri VR - Drug Des Devel Ther (2015)

Bottom Line: The present drugs used for treating obesity do not give satisfactory results, and on prolonged usage result in severe side effects.Finally, the molecules with better results were optimized for in vitro testing.The optimized lead molecule exhibited good docking score, better fit, and improved ADME profile.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus

Binding interaction and molecular dynamic simulations (MDS) between the protein 1LPB and lead after optimization.Notes: (A) The binding mode of optimized lead in the active pocket of 1LPB; (B) Ligplot of complex before MDS; (C) MDS trajectory results depicting the root-mean-square deviation (RMSD); (D) graphical representation of root-mean-square fluctuation (RMSF); (E) energy plot of the complex; and (F) binding interactions of the complex after MDS.
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f7-dddt-9-4397: Binding interaction and molecular dynamic simulations (MDS) between the protein 1LPB and lead after optimization.Notes: (A) The binding mode of optimized lead in the active pocket of 1LPB; (B) Ligplot of complex before MDS; (C) MDS trajectory results depicting the root-mean-square deviation (RMSD); (D) graphical representation of root-mean-square fluctuation (RMSF); (E) energy plot of the complex; and (F) binding interactions of the complex after MDS.

Mentions: The zinc 85893731 molecule was cleaved into two parts: an active part and an inactive part. Hydrogen was added to the active part and further minimized with an OPLS-2005 force field. After minimization, the molecular weight was checked and was 284.22 D, which was half of the lead molecule, and this satisfied the Lipinski’s rule of five. The active part was subjected to the same docking and simulation protocols implanted on the lead molecule. The same orientation was retained after XP docking with the same number of H-bonds similar to the lead molecule depicted in Figure 7A and B with a slight increase in G-score (−7.4), but the Ser152 H-bond was shifted to another atom (OH) of the same molecule after MDS. The distance between the ligand and the residue was 2.19 Å, and after a shift in the H-bond produced a small reduction in the distance, measuring 2.11 Å. Interestingly, after the MDS, a hydrogen-bond network was seen with a slight increase in the percentage of interactions, and this was mainly due to the removal of the bulky group that makes the molecule lighter and free from external forces. The RMSD, RMSF, energies plot, and interactions after MDS showed stability in the simulation studies represented in Figure 7C and F. At the same time, the fitting of the molecule was best in the binding pocket compared to previous accommodation (Figure 8). This complex was continued for 50 ns MDS, and consistency in the H-bond interaction between the important amino acid and the ligand was observed. Strikingly, 98% of the interaction with Ser152 residue was produced by the end of the 50 ns run time. This result suggested that the H-bond network in the complex became very strong with increased simulation time. The RMSD, RMSF, protein–ligand contact profiles, and the ligand-torsion profile are appended in the Supplementary material.


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

Veeramachaneni GK, Raj KK, Chalasani LM, Bondili JS, Talluri VR - Drug Des Devel Ther (2015)

Binding interaction and molecular dynamic simulations (MDS) between the protein 1LPB and lead after optimization.Notes: (A) The binding mode of optimized lead in the active pocket of 1LPB; (B) Ligplot of complex before MDS; (C) MDS trajectory results depicting the root-mean-square deviation (RMSD); (D) graphical representation of root-mean-square fluctuation (RMSF); (E) energy plot of the complex; and (F) binding interactions of the complex after MDS.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4532172&req=5

f7-dddt-9-4397: Binding interaction and molecular dynamic simulations (MDS) between the protein 1LPB and lead after optimization.Notes: (A) The binding mode of optimized lead in the active pocket of 1LPB; (B) Ligplot of complex before MDS; (C) MDS trajectory results depicting the root-mean-square deviation (RMSD); (D) graphical representation of root-mean-square fluctuation (RMSF); (E) energy plot of the complex; and (F) binding interactions of the complex after MDS.
Mentions: The zinc 85893731 molecule was cleaved into two parts: an active part and an inactive part. Hydrogen was added to the active part and further minimized with an OPLS-2005 force field. After minimization, the molecular weight was checked and was 284.22 D, which was half of the lead molecule, and this satisfied the Lipinski’s rule of five. The active part was subjected to the same docking and simulation protocols implanted on the lead molecule. The same orientation was retained after XP docking with the same number of H-bonds similar to the lead molecule depicted in Figure 7A and B with a slight increase in G-score (−7.4), but the Ser152 H-bond was shifted to another atom (OH) of the same molecule after MDS. The distance between the ligand and the residue was 2.19 Å, and after a shift in the H-bond produced a small reduction in the distance, measuring 2.11 Å. Interestingly, after the MDS, a hydrogen-bond network was seen with a slight increase in the percentage of interactions, and this was mainly due to the removal of the bulky group that makes the molecule lighter and free from external forces. The RMSD, RMSF, energies plot, and interactions after MDS showed stability in the simulation studies represented in Figure 7C and F. At the same time, the fitting of the molecule was best in the binding pocket compared to previous accommodation (Figure 8). This complex was continued for 50 ns MDS, and consistency in the H-bond interaction between the important amino acid and the ligand was observed. Strikingly, 98% of the interaction with Ser152 residue was produced by the end of the 50 ns run time. This result suggested that the H-bond network in the complex became very strong with increased simulation time. The RMSD, RMSF, protein–ligand contact profiles, and the ligand-torsion profile are appended in the Supplementary material.

Bottom Line: The present drugs used for treating obesity do not give satisfactory results, and on prolonged usage result in severe side effects.Finally, the molecules with better results were optimized for in vitro testing.The optimized lead molecule exhibited good docking score, better fit, and improved ADME profile.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus