title: Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors.
abstract: BACKGROUND
  Renin has become an attractive target in controlling hypertension because of the high specificity towards its only substrate, angiotensinogen. The conversion of angiotensinogen to angiotensin I is the first and rate-limiting step of renin-angiotensin system and thus designing inhibitors to block this step is focused in this study.
  
  
  METHODS
  Ligand-based quantitative pharmacophore modeling methodology was used in identifying the important molecular chemical features present in the set of already known active compounds and the missing features from the set of inactive compounds. A training set containing 18 compounds including active and inactive compounds with a substantial degree of diversity was used in developing the pharmacophore models. A test set containing 93 compounds, Fischer randomization, and leave-one-out methods were used in the validation of the pharmacophore model. Database screening was performed using the best pharmacophore model as a 3D structural query. Molecular docking and density functional theory calculations were used to select the hit compounds with strong molecular interactions and favorable electronic features.
  
  
  RESULTS
  The best quantitative pharmacophore model selected was made of one hydrophobic, one hydrogen bond donor, and two hydrogen bond acceptor features with high a correlation value of 0.944. Upon validation using an external test set of 93 compounds, Fischer randomization, and leave-one-out methods, this model was used in database screening to identify chemical compounds containing the identified pharmacophoric features. Molecular docking and density functional theory studies have confirmed that the identified hits possess the essential binding characteristics and electronic properties of potent inhibitors.
  
  
  CONCLUSIONS
  A quantitative pharmacophore model of predictive ability was developed with essential molecular features of a potent renin inhibitor. Using this pharmacophore model, two potential inhibitory leads were identified to be used in designing novel and future renin inhibitors as antihypertensive drugs.
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center, Research Institute of Natural Science, Plant Molecular Biology and Biotechnology Research Center, Gyeongsang National University, 501 Jinju-daero, Gazha-dong, Jinju 660-701, Republic of Korea.
authors.forename: Shalini
authors.initials: S
authors.lastname: John
authors.forename: Sundarapandian
authors.initials: S
authors.lastname: Thangapandian
authors.forename: Mahreen
authors.initials: M
authors.lastname: Arooj
authors.forename: Jong Chan
authors.initials: JC
authors.lastname: Hong
authors.forename: Kwang Dong
authors.initials: KD
authors.lastname: Kim
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000959:Antihypertensive Agents / Q000737:chemistry*; D055808:Drug Discovery; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D012084:Renin-Angiotensin System; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D008024:Ligands; D011480:Protease Inhibitors; D000092502:Renin Inhibitors