title: Active site characterization and structure based 3D-QSAR studies on non-redox type 5-lipoxygenase inhibitors.
abstract: Structure-based 3D-QSAR study was performed on a class of 5-benzylidene-2-phenylthiazolinones non-redox type 5-LOX inhibitors. In this study, binding pocket of 5-Lipoxygenase (pdb id 3o8y) was identified by manual docking using 15-LOX (pdb id 2p0m) as a reference structure. Additionally, most of the binding site residues were found conserved in both structures. These non-redox inhibitors were then docked into the binding site of 5-LOX. To generate reliable CoMFA and CoMSIA models, atom fit data base alignment method using docked conformation of the most active compound was employed. The q(2)cv and r(2)ncv values for CoMFA model were found to be 0.549 and 0.702, respectively. The q(2)cv and r(2)ncv values for the selected CoMSIA model comprised four descriptors steric, electrostatic, hydrophobic and hydrogen bond donor fields were found to be 0.535 and 0.951, respectively. Obtained results showed that our generated model was statistically reliable. Furthermore, an external test set validates the reliability of the predicted model by calculating r(2)pred i.e.0.787 and 0.571 for CoMFA and CoMSIA model, respectively. 3D contour maps generated from CoMFA and CoMSIA models were utilized to determine the key structural features of ligands responsible for biological activities. The applied protocol will be helpful to design more potent and selective inhibitors of 5-LOX.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan. Electronic address: zaheer.qasmi@iccs.edu.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul-Haq
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Naveed
authors.initials: N
authors.lastname: Khan
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Syed Kashif
authors.initials: SK
authors.lastname: Zafar
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
authors.forename: Syed Tarique
authors.initials: ST
authors.lastname: Moin
mesh_terms: D001093:Arachidonate 15-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D016208:Databases, Factual; D015195:Drug Design; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D016859:Lipoxygenase Inhibitors; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase
keywords: 3D-QSAR; 5-Benzylidene-2-phenylthiazolinone inhibitors; 5-Lipoxygenase; CoMFA; CoMSIA