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Muskal SM, Sliman J, Kokai-Kun J, et al. Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway. F1000Res. 2016;5:606doi: 10.12688/f1000research.8406.2.
Muskal, S. M., Sliman, J., Kokai-Kun, J., Pimentel, M., Wacher, V., & Gottlieb, K. (2016). Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway. F1000Research, 5606. https://doi.org/10.12688/f1000research.8406.2
Muskal, Steven M, et al. "Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway." F1000Research vol. 5 (2016): 606. doi: https://doi.org/10.12688/f1000research.8406.2
Muskal SM, Sliman J, Kokai-Kun J, Pimentel M, Wacher V, Gottlieb K. Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway. F1000Res. 2016 Apr 08;5:606. doi: 10.12688/f1000research.8406.2. eCollection 2016. PMID: 27347377.
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F1000Res. 2016 Apr 08;5:606. doi: 10.12688/f1000research.8406.2. eCollection 2016.

Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway.

F1000Research

Steven M Muskal, Joe Sliman, John Kokai-Kun, Mark Pimentel, Vince Wacher, Klaus Gottlieb

Affiliations

  1. Eidogen-Sertanty, Oceanside, CA, USA.
  2. Synthetic Biologics, Rockville, MD, USA.
  3. Cedars-Sinai Medical Center, Los Angeles, CA, USA.

PMID: 27347377 DOI: 10.12688/f1000research.8406.2

Abstract

UNLABELLED: 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.

CONCLUSION: 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.

Keywords: IBS; IBS-C; Lovastatin; homology modeling; multi-site docking

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