title: Relationships between structure and interaction kinetics for HIV-1 protease inhibitors.
abstract: The interaction between HIV-1 protease and 58 structurally diverse transition-state analogue inhibitors has been analyzed by a surface plasmon resonance based biosensor. Association and dissociation rate constants and affinities were determined and displayed as k(on)-k(off)-K(D) maps. It was shown that different classes of inhibitors fall into distinct clusters in these maps. Significant changes in association and dissociation rates were found as a result of modifying the P1/P1' or P2/P2' side chains of a linear lead compound. Similarly, cyclic urea and cyclic sulfamide inhibitors displayed different kinetic features and the affinities of both classes of cyclic compounds were limited by fast dissociation rates. These results confirm that association and dissociation rates are important features of drug-target interactions and indicate that optimization of inhibitor efficacy may be guided by aiming for high association and low dissociation rates rather than high affinity alone. The present approach thus provides a new tool for structure-interaction kinetic analysis and drug discovery.
authors.affiliation: Department of Biochemistry, Uppsala University, BMC, SE-751 23 Uppsala, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Markgren
authors.forename: Wesley
authors.initials: W
authors.lastname: Schaal
authors.forename: Markku
authors.initials: M
authors.lastname: Hämäläinen
authors.forename: Anders
authors.initials: A
authors.lastname: Karlén
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
mesh_terms: D015374:Biosensing Techniques; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D007700:Kinetics; D011485:Protein Binding; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D017320:HIV Protease Inhibitors; D014508:Urea; D016333:HIV Protease