Milan Mladenović
University of Kragujevac, Rebublic of Serbia
Title: Monoamine Oxidase B inhibitors as Leads in Parkinson’s Desease Treatment: Rational Design of Novel Scafolds Driven by Structure-Based 3-D QSAR
Biography
Biography: Milan Mladenović
Abstract
Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme’s malfunction induces oxidative damage to mitochondrial DNA and mediates development of Parkinson’s disease. Aiming to develope the novel reversible MAO B inhibitors, novel 128 compounds were rationaly designed after the modification of higly active co-crystallized coumarin inhibitor (Protein Data Bank ID: 2V61), utilizing the structure-based (SB) 3-D QSAR/SB and ligand-based (LB) alignment assesment/in vitro evaluation protocol. Coumarin 2V61 was improved by rules defined by 3-D QSAR models, generated from the available co-crystallized inhibitor-MAO B complexes, utilizing the 3-D QSAutogrid/R procedure: (1) an isobutyramide, as hydrogen-bond donnor towards MAO B Glu206, was introduced to the coumarin C3 position; (2) the C4 carbon was saturated with mixed hydrogen-bond acceptor/hydrophobic functions to interfere with recongition cage residues Tyr398 and Tyr435; (3) the C3=C4 double bond was improved with 1-methyl-6-oxopiperidine-2-carboxamide or 2-oxo-1,2,3,4-tetrahydropyrimidine-4-carboxamide rings and their methylated forms; (4) the C5 and C6 carbons were substituted by hydroxyl/methoxy functions to interact with Cys172; (5) the m-chlorobenzyloxyl moiety at C7, upgraded with o-, m-, or p-methyl groups, was retained to force the Ile199 in open conformation and to activate Phe103. Designed structures were SB LB aligned against MAO B, and six compounds were experimentally validated through synthesis and biological evaluation in vitro. Of them, two compounds, D123 (IC50 = 0.83 nM, Ki =0.25 nM) and D124 (IC50 = 0.97 nM, Ki =0.29 nM) were distinguished as potential lead candidates as anti-Parkinson’s drugs.