title: Using DFT methodology for more reliable predictive models: Design of inhibitors of Golgi α-Mannosidase II.
abstract: Human Golgi α-mannosidase II (GMII), a zinc ion co-factor dependent glycoside hydrolase (E.C.3.2.1.114), is a pharmaceutical target for the design of inhibitors with anti-cancer activity. The discovery of an effective inhibitor is complicated by the fact that all known potent inhibitors of GMII are involved in unwanted co-inhibition with lysosomal α-mannosidase (LMan, E.C.3.2.1.24), a relative to GMII. Routine empirical QSAR models for both GMII and LMan did not work with a required accuracy. Therefore, we have developed a fast computational protocol to build predictive models combining interaction energy descriptors from an empirical docking scoring function (Glide-Schrödinger), Linear Interaction Energy (LIE) method, and quantum mechanical density functional theory (QM-DFT) calculations. The QSAR models were built and validated with a library of structurally diverse GMII and LMan inhibitors and non-active compounds. A critical role of QM-DFT descriptors for the more accurate prediction abilities of the models is demonstrated. The predictive ability of the models was significantly improved when going from the empirical docking scoring function to mixed empirical-QM-DFT QSAR models (Q(2)=0.78-0.86 when cross-validation procedures were carried out; and R(2)=0.81-0.83 for a testing set). The average error for the predicted ΔGbind decreased to 0.8-1.1kcalmol(-1). Also, 76-80% of non-active compounds were successfully filtered out from GMII and LMan inhibitors. The QSAR models with the fragmented QM-DFT descriptors may find a useful application in structure-based drug design where pure empirical and force field methods reached their limits and where quantum mechanics effects are critical for ligand-receptor interactions. The optimized models will apply in lead optimization processes for GMII drug developments.
authors.affiliation: Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovak Republic; Department of Physical and Theoretical Chemistry, Faculty of Natural Sciences, Comenius University, Mlynská dolina CH-1, Ilkovičova 6, 842 15 Bratislava, Slovak Republic. Electronic address: chembobo@savba.sk.
authors.forename: Adela
authors.initials: A
authors.lastname: Bobovská
authors.affiliation: Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovak Republic. Electronic address: chemitsa@savba.sk.
authors.forename: Igor
authors.initials: I
authors.lastname: Tvaroška
authors.affiliation: Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences, Dúbravska cesta 9, 845 38 Bratislava, Slovak Republic. Electronic address: chemkona@savba.sk.
authors.forename: Juraj
authors.initials: J
authors.lastname: Kóňa
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D043323:alpha-Mannosidase / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D043323:alpha-Mannosidase
keywords: Cancer; Density functional theory; Linear interaction energy; Mannosidase; Selective inhibition; Structure-based drug design