title: Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway.
abstract: Methane produced by the methanoarchaeon Methanobrevibacter smithii ( M. smithii) has been linked to constipation, irritable bowel syndrome with constipation (IBS-C), and obesity. Lovastatin, which demonstrates a cholesterol-lowering effect by the inhibition of HMG-CoA reductase, may also have an anti-methanogenesis effect through direct inhibition of enzymes in the archaeal methanogenesis pathway. We conducted protein-ligand docking experiments to evaluate this possibility. Results are consistent with recent clinical findings.
  
  
  METHODS
  F420-dependent methylenetetrahydromethanopterin dehydrogenase ( mtd), a key methanogenesis enzyme was modeled for two different methanogenic archaea: M. smithii and Methanopyrus kandleri. Once protein models were developed, ligand-binding sites were identified. Multiple ligands and their respective protonation, isomeric and tautomeric representations were docked into each site, including F420-coenzyme (natural ligand), lactone and β-hydroxyacid forms of lovastatin and simvastatin, and other co-complexed ligands found in related crystal structures.
  
  
  RESULTS
  1) Generally, for each modeled site the lactone form of the statins had more favorable site interactions compared to F420; 2) The statin lactone forms generally had the most favorable docking scores, even relative to the native template PDB ligands; and 3) The statin β-hydroxyacid forms had less favorable docking scores, typically scoring in the middle with some of the F420 tautomeric forms. Consistent with these computational results were those from a recent phase II clinical trial ( NCT02495623) with a proprietary, modified-release lovastatin-lactone (SYN-010) in patients with IBS-C, which showed a reduction in symptoms and breath methane levels, compared to placebo.
  
  
  CONCLUSIONS
  The lactone form of lovastatin exhibits preferential binding over the native-F420 coenzyme ligand in silico and thus could inhibit the activity of the key M. smithii methanogenesis enzyme mtd in vivo. Statin lactones may thus exert a methane-reducing effect that is distinct from cholesterol lowering activity, which requires HMGR inhibition by statin β-hydroxyacid forms.
authors.affiliation: Eidogen-Sertanty, Oceanside, CA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Muskal
authors.affiliation: Synthetic Biologics, Rockville, MD, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Sliman
authors.affiliation: Synthetic Biologics, Rockville, MD, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kokai-Kun
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Pimentel
authors.affiliation: Synthetic Biologics, Rockville, MD, USA.
authors.forename: Vince
authors.initials: V
authors.lastname: Wacher
authors.affiliation: Synthetic Biologics, Rockville, MD, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Gottlieb
keywords: IBS; IBS-C; Lovastatin; homology modeling; multi-site docking