Picolinic Acids as Inhibitors of Dopamine b-Monooxygenase: QSAR and Putative Binding Site

Abstract

Dopamine b-monooxygenase (DBM, EC 1.14.17.1) catalyzes the oxidn. 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 compds. were investigated by Hansch anal. and comparative mol. field anal. (CoMFA). The correlation of pI50 values with electronic (nucleophilic substituent const. sp-, oxygen net charges and HOMO energy calcd. by AMPAC-AM1), hydrophobic (p values of R4) and steric descriptors (molar refraction and Sterimol parameters of R5) indicated that a more neg. charged carboxylate moiety, more lipophilic R4 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 homol. model of DBM derived from a crystal structure of peptidylglycine a-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. R4 points to a tyrosine side chain. R5 protrudes into the fringe of the catalytic crevice. It may "freeze" to the solvated surface of polar amino acids and addnl. contact an isoleucine residue. Taken together, the model explains the QSAR results by corresponding types of interaction.