Journal article Open Access

Molecular Dynamic Simulation and Receptor-based Pharmacophore Modeling on Human Renin for Discovery of Novel Inhibitors

Chanin Park; Sundarapandian Thangapandian; Yuno Lee; Minky Son; Shalini John; Young-sik Sohn; Keun Woo Lee

Hypertension is characterized with stress on the heart and blood vessels thus increasing the risk of heart attack and renal diseases. The Renin angiotensin system (RAS) plays a major role in blood pressure control. Renin is the enzyme that controls the RAS at the rate-limiting step. Our aim is to develop new drug-like leads which can inhibit renin and thereby emerge as therapeutics for hypertension. To achieve this, molecular dynamics (MD) simulation and receptor-based pharmacophore modeling were implemented, and three rennin-inhibitor complex structures were selected based on IC50 value and scaffolds of inhibitors. Three pharmacophore models were generated considering conformations induced by inhibitor. The compounds mapped to these models were selected and subjected to drug-like screening. The identified hits were docked into the active site of renin. Finally, hit1 satisfying the binding mode and interaction energy was selected as possible lead candidate to be used in novel renin inhibitors.

Files (1.6 MB)
Name Size
1.6 MB Download
  • Cooper ME, "The role of the renin-angiotensin-aldosterone system in diabetes and its vascular complications," American journal of hypertension,vol. 17, pp. S16-S20, 2004.
  • Dzau V, "The cardiovascular continuum and renin-angiotensin-aldosterone system blockade," Journal of hypertension,vol. 23, S9, 2005.
  • James MNG, Sielecki AR,"Stereochemical analysis of peptide bond hydrolysis catalyzed by the aspartic proteinase penicillopepsin,"Biochemistry,vol. 24, no. 14, pp. 3701-3713, 1985. [10] Stanton A, "Therapeutic potential of renin inhibitors in the management of cardiovascular disorders," American Journal of Cardiovascular Drugs,vol. 3, no. 6, pp. 389-394, 2003. [11] Fisher NDL, Hollenberg NK, "Is there a future for renin inhibitors?," Expert Opinion on Investigational Drugs,vol. 10, no. 3, pp. 417-426, 2001. [12] Wood JM, Maibaum J, Rahuel J, Grutter MG, Cohen NC, Rasetti V, Ruger H, Goschke R, Stutz S, Fuhrer W, "Structure-based design of aliskiren, a novel orally effective renin inhibitor," Biochemical and biophysical research communications,vol. 308, no. 4, pp. 698-705, 2003. [13] Udenigwe CC, Li H, Aluko RE, "Quantitative structure-activity relationship modeling of renin-inhibiting dipeptides," Amino Acids, pp. 1-8, 2011. [14] Claude Cohen N, "Structure-Based Drug Design and the Discovery of Aliskiren (Tektuma): Perseverance and Creativity to Overcome a RD Pipeline Challenge," Chemical Biology & Drug Design,vol. 70, no. 6, pp. 557-565, 2007. [15] Bezenc on 0, Bur D, Weller T, Richard-Bildstein S, Remen L, Sifferlen T, Corminboeuf 0, Grisostomi C, Boss C, Prade L, "Design and Preparation of Potent, Nonpeptidic, Bioavailable Renin Inhibitors," Journal of Medicinal Chemistry,vol. 52, no. 12, pp. 3689-3702, 2009. [16] Deng J, Lee KW, Sanchez T, Cui M, Neamati N, Briggs JM, "Dynamic receptor-based pharmacophore model development and its application in designing novel HIV-1 integrase inhibitors," Journal of Medicinal Chemistry,vol. 48, no. 5, pp. 1496-1505, 2005. [17] Tice CM, Xu Z, Yuan J, Simpson RD, Cacatian ST, Flaherty PT, Zhao W, Guo J, Ishchenko A, Singh SB, "Design and optimization of renin inhibitors: Orally bioavailable alkyl amines," Bioorganic & medicinal chemistry letters,vol. 19, no. 13, pp. 3541-3545, 2009. [18] Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC, "GROMACS: fast, flexible, and free," Journal of computational chemistry,vol. 26, no. 16, pp. 1701-1718, 2005. [19] Schuttelkopf AW, Van Aalten DMF, "PRODRG: a tool for high-throughput crystallography of protein-ligand complexes," ActaCrystallographica Section D: Biological Crystallography,vol. 60, no. 8, pp. 1355-1363, 2004. [20] Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG, "A smooth particle mesh Ewald method," Journal of Chemical Physics,vol. 103, no. 19, pp. 8577-8593, 1995. [21] Hess B, Bekker H, Berendsen HJC, Fraaije JGEM, "L1NCS: a linear constraint solver for molecular simulations," Journal of computational chemistry,vol. 18, no. 12, pp. 1463-1472, 1997. [22] Miyamoto S, Kollman PA, "SETTLE: an analytical version of the SHAKE and RATTLE algorithm for rigid water models," Journal of computational chemistry,vol. 13, no. 8, pp. 952-962, 1992. [23] Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD, "Improved protein-ligand docking using GOLD," Proteins: Structure, Function, and Bioinformatics,vol. 52, no. 4, pp. 609-623, 2003.
  • Kim S, Iwao H, "Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases," Pharmacological reviews,vol. 52, no. 1, pp. 11, 2000.
  • Murray CJL, Lopez AD, "Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study," The Lancet, vol.349, no.9064, pp.1498-1504, 1997.
  • Norris K, Vaughn C, "The role of reninangiotensin aldosterone system inhibition in chronic kidney disease," Expert review of cardiovascular therapy,vol. 1, no. 1, pp. 51-63, 2003.
  • Rahuel J, Rasetti V, Maibaum J, Rueger H, Goschke R, Cohen N, Stutz S, Cumin F, Fuhrer W,"Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin,"Chemistry & Biology,vol. 7, no. 7, pp. 493-504, 2000.
  • Sielecki AR, Hayakawa K, Fujinaga M, Murphy M, Fraser M, Muir AK, Carilli CT, Lewicki JA, Baxter JD, James M, "Structure of recombinant human renin, a target for cardiovascular-active drugs, at 2.5 A resolution," Science,vol. 243, no. 4896, pp. 1346, 1989.
  • Wood JM, Stanton JL, Hofbauer KG, "Inhibitors of renin as potential therapeutic agents," Journal of enzyme inhibition,vol. 1, no. 3, pp. 169, 1987.
All versions This version
Views 11
Downloads 00
Data volume 0 Bytes0 Bytes
Unique views 11
Unique downloads 00


Cite as