title: Experimental and 'in silico' analysis of the effect of pH on HIV-1 protease inhibitor affinity: implications for the charge state of the protein ionogenic groups.
abstract: The pH dependence of the HIV-1 protease inhibitor affinity was studied by determining the interaction kinetics of a series of inhibitors at three pH values by surface plasmon resonance (SPR) biosensor analysis. The results were rationalized by molecular mechanics based protocols that have as a starting point the structures of the HIV-1 protease inhibitor complexes differing in the protonation states as predicted by our calculations. The SPR experiments indicate a variety of binding affinity pH dependencies which are rather well reproduced by our simulations. Moreover, our calculations are able to pinpoint the possible changes in the charged state of the protein binding site and of the inhibitor that underlie the observed effects of the pH on binding affinity. The combination of SPR and molecular mechanics calculations has afforded novel insights into the pH dependence of inhibitor interactions with their target. This work raises the possibility of designing inhibitors with different pH binding affinity profiles to the ones described here.
authors: Departamento de Química Orgánica, Facultad de Química, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors: José L
authors: JL
authors: Domínguez
authors: Thomas
authors: T
authors: Gossas
authors: M
authors: M
authors: Carmen Villaverde
authors: U
authors: U
authors: Helena Danielson
authors: Fredy
authors: F
authors: Sussman
mesh_terms: D015374:Biosensing Techniques; D020134:Catalytic Domain / Q000187:drug effects; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D020349:Surface Plasmon Resonance
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease