Novel inhibitors of As(III) S-adenosylmethionine methyltransferase (AS3MT) identified by virtual screening

Roland W Bürli; Huijun Wei; Glen Ernst; Abigail Mariga; Ian M Hardern; Kara Herlihy; Alan J Cross; Steven S Wesolowski; Hongming Chen; Ronald D G McKay; Daniel R Weinberger; Nicholas J Brandon; James C Barrow

doi:10.1016/j.bmcl.2018.08.012

Novel inhibitors of As(III) S-adenosylmethionine methyltransferase (AS3MT) identified by virtual screening

Bioorg Med Chem Lett. 2018 Oct 15;28(19):3231-3235. doi: 10.1016/j.bmcl.2018.08.012. Epub 2018 Aug 14.

Authors

Affiliations

¹ Neuroscience, IMED Biotech Unit, AstraZeneca, Cambridge CB21 6GH, UK. Electronic address: roland.burli@azneuro.com.
² Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA.
³ Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge CB4 0WG, UK.
⁴ Neuroscience, IMED Biotech Unit, AstraZeneca Boston, Waltham, MA 02451, USA.
⁵ Discovery Sciences, IMED Biotech Unit, AstraZeneca Gothenburg, S-43183 Mölndal, Sweden.
⁶ Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA; Departments of Psychiatry, Neurology, Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁷ Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, MD 21205, USA; Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, MD 21287, USA. Electronic address: james.barrow@libd.org.

PMID: 30170942
DOI: 10.1016/j.bmcl.2018.08.012

Abstract

Due to increased interest in As(III) S-adenosylmethionine methyltransferase (AS3MT), a search for chemical probes that can help elucidate function was initiated. A homology model was built based on related enzymes, and virtual screening produced 426 potential hits. Evaluation of these compounds in a functional enzymatic assay revealed several modest inhibitors including an O-substituted 2-amino-3-cyano indole scaffold. Two iterations of near neighbor searches revealed compound 5 as a potent inhibitor of AS3MT with good selectivity over representative methyltransferases DOT1L and NSD2 as well as a representative set of diverse receptors. Compound 5 should prove to be a useful tool to investigate the role of AS3MT and a potential starting point for further optimization.

Keywords: Arsenic methyltransferase; As(III) S-adenosylmethionine methyltransferase; Methyltransferase; Schizophrenia; Virtual screening.

MeSH terms

Enzyme Inhibitors / pharmacology*
Humans
Methyltransferases / antagonists & inhibitors*

Substances

Enzyme Inhibitors
Methyltransferases
AS3MT protein, human