LIGAND BASED PHARMACOPHORE MODELING, VIRTUAL SCREENING AND MOLECULAR DOCKING STUDIES TO DESIGN NOVEL PANCREATIC LIPASE INHIBITORS
Objective: To understand the essential structural features required for pancreatic lipase (PL) inhibitory activity and to design novel chemical entities, ligand-based pharmacophore modeling, virtual screening and docking studies were carried out.
Methods: The pharmacophore model was generated based on 133 compounds with PL inhibitory activity using PHASE. An external test set and decoy dataset methods were applied to validate the hypothesis and to retrieve potential PL inhibitors. The generated hypothesis model was further subjected to virtual screening and molecular docking studies.
Results: A five point pharmacophoric hypothesis model which consists of three hydrogen bond acceptor sites and two hydrophobic sites was developed. The generated pharmacophore gave significant 3D QSAR (three-dimensional Quantitative Structural Activity Relationship) model with r2 of 0.9389 and Q2 value of 0.4016. After database screening, five molecules were found to have better glide scores and binding interactions with the active site amino acid residues.
Conclusion: As an outcome of this study, five hit molecules were suggested as potent PL inhibitors as they showed good glide scores as well as binding interactions with required active site amino acids. The five molecules obtained from this study may serve as potential leads for the development of promising anti-obesity agents.Â
2. Cheung BM. Drug treatment for obesity in the post-sibutramine era. Drug Saf 2011;34:641-50.
3. Remesh A. Obesity: pathophysiology and management-A pharmacological perspective. Asian J Pharm Clin Res 2013;6:11-3.
4. Cheung BM, Cheung T, Samaranayake NR. Safety of antiobesity drugs. Ther Adv Drug Saf 2013;4:171-81.
5. Heal DJ, Gosden J, Smith SL. A review of late-stage CNS drug candidates for the treatment of obesity. Int J Obes 2013;371:107-17.
6. BorgstrÃ¶m B. Mode of action of tetrahydrolipstatin. a derivative of the naturally occurring lipase inhibitor lipstatin. Biochim Biophys Acta 1988;962:308-16.
7. Shi Y, Burn P. Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nat Rev Drug Discovery 2004;3:695-10.
8. Harrison SA, Fincke C, Helinski D, Torgerson S, Hayashi P. A pilot study of orlistat treatment in obese, non-alcoholic steatohepatitis patients. Aliment Pharmacol Ther 2004;20:623-8.
9. Torgerson JS, Hauptman J, Boldrin MN, SjÃ¶strÃ¶m L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27:155-61.
10. Caporuscio F, Tafi A. Pharmacophore modelling: a forty-year-old approach and its modern synergies. Curr Med Chem 2011;18:2543-53.
11. Del Rio A, Barbosa AJ, Caporuscio F, Mangiatordi GF. CoCoCo: a free suite of multi-conformational chemical databases for high-throughput virtual screening purposes. Mol Biosyst 2010;6:2122-8.
12. Chen Z, Li HL, Zhang QJ, Bao XG, Yu KQ, Luo XM, et al. Pharmacophore-based virtual screening versus docking-based virtual screening: a benchmark comparison against eight targets. Acta Pharmacol Sin 2009;30:1694-708.
13. Kim JH, Kim HJ, Kim C, Jung H, Kim YO, Ju JY, et al. Development of lipase inhibitors from various derivatives of monascus pigment produced by Monascus fermentation. Food Chem 2007;101:357-64.
14. Wei K, Wang GQ, Bai X, Niu YF, Chen HP, Wen CN, et al. Structure-based optimization and biological evaluation of pancreatic lipase inhibitors as novel potential antiobesity agents. Nat Prod Bioprospect 2015;5:129-57.
15. Liang LF, Wang T, Cai YS, He WF, Sun P, Li YF, et al. Brominated polyunsaturated lipids from the Chinese sponge Xestospongia testudinaria as a new class of pancreatic lipase inhibitors. Eur J Med Chem 2014;22:290-7.
16. Ahn JH, Liu Q, Lee C, Ahn M, Yoo HS, Hwang BY, et al. A new pancreatic lipase inhibitor from Broussonetia kanzinoki. Bioorg Med Chem Lett 2012;22(8, Suppl 1):2760-3.
17. Jeong JY, Jo YH, Kim SB, Liu Q, Lee JW, Mo EJ, et al. Pancreatic lipase inhibitory constituents from Morus alba leaves and optimization for extraction conditions. Bioorg Med Chem Lett 2015;25(11, Suppl 1):2269-74.
18. Kim YM, Lee EW, Eom SH, Kim TH. Pancreatic lipase inhibitory stilbenoids from the roots of Vitis vinifera. Int J Food Sci Nutr 2014;65:97-100.
19. Dixon SL, Smondyrev AM, Rao SN. PHASE: a novel approach to pharmacophore modeling and 3D database searching. Chem Biol Drug Des 2006;67:370-2.
20. Shivakumar D, Williams J, Wu Y, Damm W, Shelly J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics Free energy pertubation and the OPLS force field. J Chem Theory Comput 2010;6:1509-19.
21. Shah UA, Deokar HS, Kadam SS, Kulkarni VM. Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl) pyrimidines as COX-2 inhibitors. Mol Divers 2010;14:559-68.
22. Wolber G, Seidel T, Bendix F, Langer T. Molecule-pharmacophore superpositioning and pattern matching in computational drug design. Drug Discovery Today 2008;13:23-9.
23. Zhang J, Liu G, Tang Y. Chemical function-based pharmacophore generation of selective kappa-opioid receptor agonists by catalyst and phase. J Mol Model 2009;15:1027-41.
24. Umamatheswari S, Balaji B, Ramanathan M, Kabilan S. Synthesis, antimicrobial evaluation and QSAR studies of novel piperidin-4-yl-5-spiro-thiadiazoline derivatives. Bioorg Med Chem Lett 2010;20:6909-14.
25. Mysinger MM, Carchia M, Irwin JJ, Shoichet BK. Directory of useful decoys, enhanced (DUD-E): better ligands and decoys for better benchmarking. J Med Chem 2012;55:6582-94.
26. Egloff MP, Marguet F, Buono G, Verger R, Cambillau C, van Tilbeurgh H. The 2.46 AÂ° resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate. Biochem 1995;34:2751-62.
27. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye L, Pollard WT, Banks JL. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 2004;47:1750-9.
28. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 2004;47:1739-49.
29. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem 2006;49:6177-96.
30. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 2000;44:235-49.
31. Yang Y, Lowe ME. The open lid mediates pancreatic lipase function. J Lipid Res 2000;41:48-57.
32. Thomas A, Allouche M, Basyn F, Brasseur R, Kerfelec B. Role of the lid hydrophobicity pattern in pancreatic lipase activity. J Biol Chem 2005;280:40074-83.
33. Miled N, Canaan S, Dupuis L, Roussel A, RiviÃ¨re M, CarriÃ¨re F, et al. Digestive lipases: from three-dimensional structure to physiology. Biochimie 2000;82:973-86.
34. Winkler FK, D'Arcy A, Hunziker W. Structure of human pancreatic lipase. Nature 1990;343:771-4.
35. LÃ¼thi-Peng Q, Marki HP, HadvÃ¡ry P. Identification of the active-site serine in human pancreatic lipase by chemical modification with tetrahydrolipstatin. FEBS Lett 1992;299:111-5.
36. Van Tilbeurgh H, Sarda L, Verger R, Cambillau C. Structure of the pancreatic lipase-procolipase complex. Nature 1992;359:159-62.
37. Bezzine S, Carriere F, De Caro J, Verger R, De Caro A. Human pancreatic lipase: an exposed hydrophobic loop from the C-terminal domain may contribute to interfacial binding. Biochem 1998;37:11846-55.
38. Bouchagra S, Benamia F, Djeghaba Z. Docking studies of (-)-Epigallocatechin-3-gallate a potential non-competitive pancreatic Lipase inhibitor. Res J Pharm Biol Chem Sci 2016;7:2493-505.
39. Mohammad M, Al-Masri IM, Issa A, Khdair A, Bustanji Y. Inhibition of pancreatic lipase by berberine and dihydroberberine: an investigation by docking simulation and experimental validation. Med Chem Res 2012;22:2273-8.