title: A docking study of L-chicoric acid with HIV-1 integrase.
abstract: Human immunodeficiency virus 1 integrase (HIV-1 IN) is the enzyme responsible for integrating the viral DNA into the host genome, and is essential to the replication of the virus. L-Chicoric acid (L-CA) is a bidentate catechol that has been identified as a potent inhibitor of HIV-1 IN. Using the new Autodock 4.0 free-energy function we have obtained a L-CA binding mode that explains its observed potency and is consistent with available experimental data. Because of the alpha,beta-unsaturated ester functionality of the side arms of L-CA we first performed an extensive conformational analysis of L-CA using semiempirical and ab initio calculations. As a result we have identified two distinct L-CA binding modes, one for the s-cis/s-cis and another for the s-cis/s-trans isomers. The most stable conformer was found to be the structure with the alpha,beta-unsaturated ester in the s-cis conformation for both arms of L-CA. This conformer also gave the top-ranked docking solution. Analysis of the interactions with key IN residues, combined with results using a L-CA tetraacetylated derivative and a Q148A IN mutant, correlate well with the experimental data.
authors.affiliation: Department of Chemistry, St. Edward's University, Austin, TX 78704, USA. healy@stedwards.edu
authors.forename: Eamonn F
authors.initials: EF
authors.lastname: Healy
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sanders
authors.forename: Peter J
authors.initials: PJ
authors.lastname: King
authors.forename: W Edward
authors.initials: WE
authors.lastname: Robinson
mesh_terms: D002109:Caffeic Acids / Q000737:chemistry*; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D013237:Stereoisomerism; D013386:Succinates / Q000737:chemistry*
chemical_list: D002109:Caffeic Acids; D019428:HIV Integrase Inhibitors; D013386:Succinates; D019427:HIV Integrase; C100435:chicoric acid