Transient binding patches: a plausible concept for drug binding

Journal of Chemical Biology

Heino Prinz¹  André Schönichen¹ 

[1] Max-Planck-Institut für Molekulare Physiologie, Otto-Hahn-Str. 11, 44227 Dortmund, Germany

关键词: Dose–response curves;    Hill coefficients;    Enzymatic activity;    Ligand binding;   

DOI  :  10.1007/s12154-008-0011-5

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

Dose–response curves for inhibitors (drugs) generally are analyzed by means of four-parameter fits, yielding IC50, background, amplitude, and Hill coefficient. Hill coefficients ≠1 contradict 1:1 competition. If binding of substrates to proteins is a stepwise process where initial binding to initial locations (patches) leads to strong binding on defined sites, then drugs (non-endogenous inhibitors) may bind to those presumably larger patches and need not follow a 1:1 stoichiometry for specific inhibition. This concept was translated into three computable models and successfully fitted to 1,282 phosphatase dose–response curves. The models only required four parameters, namely, the equilibrium dissociation constant KD(1) of the first inhibitor binding step, background, amplitude, and a compound interaction factor to quantify the interaction of inhibitors on those patches. Binding of one established inhibitor to the vaccinia virus VH1-related (VHR) phosphatase was directly measured with microcalorimetry, confirming multiple inhibitor binding with equilibrium constants obtained from corresponding inhibition curves.

【 授权许可】

Unknown