title: Designing Hydroxamates and Reversed Hydroxamates to Inhibit Zinc-containing Proteases but not Cytochrome P450s: Insights from Quantum Mechanics and Protein-ligand Crystal Structures.
abstract: The Hydroxamate is a useful functional group that binds to metals in a range of enzymes, notably zinc in matrix metalloproteases and histone deacetylases. The group is also able to form interactions with iron leading to inhibition of the cytochromes P450, particularly the 3A4 isoform. We have studied the available crystal structures of zinc-containing proteins bound to hydroxamates and compared the observed geometries with those found by quantum mechanical calculations. This has revealed the likely binding mode preferences for neutral and anionic protonation states and highlighted the importance of electrostatic complementarity. Calculations were also performed for the interaction of the hydroxamate with iron in a heme environment, as found in the cytochromes P450. These reveal that the preferred binding mode of hydroxamates in this environment involves the s-trans conformation. These calculations provide design guidelines for those interested in designing inhibitors of metalloenzymes that do not block metabolism of other drugs. The ability to predict the geometries and energies of binding modes that cannot be studied experimentally is an advantage offered by this kind of study.
authors.affiliation: Charlotte Barker, Iva Lukac, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Barker
authors.affiliation: Charlotte Barker, Iva Lukac, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Iva
authors.initials: I
authors.lastname: Lukac
authors.affiliation: Andrew G. Leach, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool, L3 3AF, UK phone:+44 (0)1512312404. a.g.leach@ljmu.ac.uk.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Leach
mesh_terms: D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry; D006418:Heme / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D007501:Iron / Q000737:chemistry; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D006418:Heme; D007501:Iron; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D045726:Metalloproteases; D015032:Zinc
keywords: Ab initio calculations; Metalloenzymes; Structural Biology