title: Design of 1-arylsulfamido-2-alkylpiperazine derivatives as secreted PLA2 inhibitors.
abstract: Structure and analog based analysis of 3D-QSAR, CoMFA and CoMSIA, along with different docking protocols were used to evaluate the structure activity relationship of 26 analogues of 1-aryl sulfamido-2-alkyl piperazines to model the activities of group I and II secreted phospholipases A(2) (sPLA(2)s) and probe into the chemical space and nature of receptor--ligand interactions. The best CoMFA model yields cross-validated (q(2)) and conventional correlation coefficients (r(2)) of 0.703 and 0.962 respectively whereas CoMSIA model yields q(2) and r(2) values of 0.408 and 0.922 respectively, followed by docking analysis using FlexX and GOLD methodologies on the X-ray structure of human and bovine PLA(2)s. A comparative study was made to find out the differences in the active site residues of both PLA(2)s. The information enunciated from the analysis of CoMFA and CoMSIA maps and docking results were analyzed and employed in the design of 29 new ligands using molecules 4, 21, 22 from the initial set as templates. New ligands for group I and II secreted phospholipases A(2) (sPLA(2)s) have been thus designed based on the 32 analogues of 1-aryl sulfamido-2-alkyl piperazine with a cursory note on its synthetic feasibility. Molecular modeling studies indicate that the newly designed ligands are expected to show high affinity and experimental efforts in this direction is highly rewarding.
authors.affiliation: Molecular Modeling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India.
authors.forename: Preethi
authors.initials: P
authors.lastname: Badrinarayan
authors.forename: P
authors.initials: P
authors.lastname: Srivani
authors.forename: G
authors.initials: G
authors.lastname: Narahari Sastry
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain / Q000187:drug effects; D002417:Cattle; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D064801:Phospholipase A2 Inhibitors; D054467:Phospholipases A2 / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D064801:Phospholipase A2 Inhibitors; D010879:Piperazines; D013449:Sulfonamides; D054467:Phospholipases A2