Picolinic acids as inhibitors of dopamine beta-monooxygenase: QSAR and putative binding site

Dopamine beta-monooxygenase (DBM, EC 1.14.17.1) catalyzes the oxidation of dopamine into (R)-noradrenaline. DBM inhibitors may act as antihypertensive drugs. A series of 22 picolinic acids substituted in 4- and 5-position was previously synthesized and tested for inhibition of DBM from bovine adrenal medulla. The QSAR of these compounds were investigated by Hansch analysis and comparative molecular field analysis (CoMFA). The correlation of pI(50) values with electronic (nucleophilic substituent constant sigma(p) (-), oxygen net charges and highest occupied molecular orbital energy calculated by AMPAC-AM1), hydrophobic (pi values of R(4)) and steric descriptors (molar refraction and Sterimol parameters of R(5)) indicated that a more negatively charged carboxylate moiety, more lipophilic R(4) groups as well as wider bulk and higher molar refraction of 5-substituents increase DBM inhibition. The CoMFA approach generally reproduced these QSAR in terms of steric and electrostatic field variables, the latter restricted to the carboxylate area. To predict a putative binding site, dopamine and fusaric acid were docked into a partial homology model of DBM derived from a crystal structure of peptidylglycine alpha-hydroxylating monooxygenase (EC 1.14.17.3). The inhibitor is suggested to interact by its carboxylate group with the copper site CuB and the protonated amino group of dopamine according to the uncompetitive type of inhibition. R(4) points to a tyrosine side chain. R(5) protrudes into the fringe of the catalytic crevice. It may "freeze" to the solvated surface of polar amino acids and additionally contact an isoleucine residue. Taken together, the model explains the QSAR results by corresponding types of interaction.