title: Synergistic effects in the designs of neuraminidase ligands: analysis from docking and molecular dynamics studies.
abstract: Docking and molecular dynamics were used to study the nine ligands (see Scheme 1) at the neuraminidase (NA) active sites. Their binding modes are structurally and energetically different, with details given in the text. Compared with 1A (oseltamivir carboxylate), the changes of core template or/and functional groups in the other ligands cause the reductions of interaction energies and numbers of H-bonds with the NA proteins. Nonetheless, all these ligands occupy the proximity space at the NA active sites and share some commonness in their binding modes. The fragment approach was then used to analyze and understand the binding specificities of the nine ligands. The contributions of each core template and functional group were evaluated. It was found that the core templates rather than functional groups play a larger role during the binding processes; in addition, the binding qualities are determined by the synergistic effects of the core templates and functional groups. Among the nine ligands, 1A (oseltamivir carboxylate) has the largest synergistic energy and its functional groups fit perfectly with the NA active site, consistent with the largest interaction energy, numerous H-bonds with the NA active-site residues as well as experimentally lowest IC(50) value. Owing to the poorer metabolizability than oseltamivir, large contribution of the benzene core template and fine synergistic effects of the functional groups, the 4-(N-acetylamino)-5-guanidino-3-(3-pentyloxy)benzoic acid should be an ideal lead compound for optimizing NA drugs.
authors.affiliation: Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, PR China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Yang
authors.forename: Yingkun
authors.initials: Y
authors.lastname: Nie
authors.forename: Gang
authors.initials: G
authors.lastname: Yang
authors.forename: Yuangang
authors.initials: Y
authors.lastname: Zu
authors.forename: Yujie
authors.initials: Y
authors.lastname: Fu
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhou
mesh_terms: D000146:Acids, Carbocyclic; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D053138:Cyclohexenes / Q000737:chemistry / Q000494:pharmacology; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D007251:Influenza, Human / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D009975:Orthomyxoviridae / Q000187:drug effects; D053139:Oseltamivir / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000146:Acids, Carbocyclic; D001565:Benzoates; D053138:Cyclohexenes; D003517:Cyclopentanes; D006146:Guanidines; D008024:Ligands; D053139:Oseltamivir; D009439:Neuraminidase; C535162:oseltamivir carboxylate; C414210:peramivir