title: Discovery of multitarget inhibitors by combining molecular docking with common pharmacophore matching.
abstract: Multitarget drugs have been to be found effective in controlling complex diseases. However, how to design multitarget drugs presents a great challenge. We have developed a computer-assisted strategy to screen for multitarget inhibitors using a combination of molecular docking and common pharmacophore matching. This strategy was successfully applied to screen for dual-target inhibitors against both the human leukotriene A(4) hydrolase (LTA4H-h) and the human nonpancreatic secretory phospholipase A2 (hnps-PLA2). Three compounds screened from the chemical database MDL Available Chemical Directory were found to inhibit these two enzymes at the 10 microM level. Moreover, one synthetic compound matching the common pharmacophores inhibits LTA4H-h and hnps-PLA2 with IC(50) values of 35 nM and 7.3 microM, respectively. The common pharmacophore model can also be used to search small molecule databases or collections of existing inhibitors, as well as to guide combinatorial library design to search for ideal multitarget inhibitors.
authors.affiliation: Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Dengguo
authors.initials: D
authors.lastname: Wei
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Jiang
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Chong
authors.initials: C
authors.lastname: He
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Pei
authors.forename: Luhua
authors.initials: L
authors.lastname: Lai
mesh_terms: D055592:Biophysical Phenomena; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D004851:Epoxide Hydrolases / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D054467:Phospholipases A2 / Q000737:chemistry*; D011485:Protein Binding
chemical_list: D054467:Phospholipases A2; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase