Computational study of the monoamine oxidase B mechanism-based irreversible inhibitors

Pozadina: Monoamin oksidaza B (MAO-B) flavoenzim je odgovoran za metabolizam endogenih i egzogenih amina, uključujući monoaminske neutransmitere čija je narušena homeostaza implicirana kod razvitka mnogih neurodegenerativnih oboljenja. MAO-B predstavlja osnovnu farmakološku metu za liječenje Alzheimerove i Parkinsonove bolesti. Komercijalni lijekovi, selegilin i razagilin, administriraju se uz dijetalne restrikcije te, u većim dozama, gube selektivnost što rezultira učestalijim nuspojavama većeg intenziteta. Stoga, postoji pritisak tržišta za razvitkom novih, mehanizmom temeljenih inhibitora MAO-B enzima. Rezultati: Inovativni pristup razvijen je za dizajn novih inhibitora te uključuje spajanje temeljnih aromatskih struktura s propargilaminskom jezgrom koja je prisutna kod komercijalno dostupnih lijekova koji ciljaju MAO enzime. Metodom molekulskog pristajanja i potom simulacijama molekulske dinamike, dobiven je povoljniji termodinamički profil vezanja novodizajniranog liganda N-metil-N-propargil-2-indol (42Me) na aktivno mjesto MAO-B. Optimalniji kinetički profili inhibitorne aktivnosti spoja 42Me okarakteriziran je mehanističkim DFT izračunima na klaster modelu MAO-B enzima. Sprovođenjem populacijske analize liganda, potvrđen je mehanizam hidridne apstrakcije prvog koraka inhibicijske reakcije na temelju referentnog liganda koji ima dobro poznat mehanizam vezanja. Zaključak: Dobiveni rezultati ukazuju na to da je novodizajnirani ligand 42Me kinetički te termodinamički povoljniji propargilaminski inhibitor MAOB (MAOI) od postojećih lijekova, selegilina i razagilina. Reakcija inhibicije MAO-B enzima s kandidatom 42Me efikasija je 69x naspram selegilina, odnosno 622x od razagilina. Primijenjen dizajn propargilaminskih MAOI pokazao se uspješnim te će dobiveni rezultati pomoći u daljnjem razvoju inhibitora poboljšanih kinetičkih i termodinamičkih parametara.Background: Monoamine oxidase B (MAO-B) is a flavoenzyme responsible for the metabolism of endogenic and exogenic amines such as monoamine neurotransmitters whose disturbed homeostasis is implicated in the wide range of neurodegenerative pathogenesis. MAO-B represents a primary pharmacological target for the treatment of Alzheimer's and Parkinson's disease. Commercial drugs, selegiline, and rasagiline, are administrated with dietary restrictions and in high doses are associated with more frequent and greater intensity side effects. There is a constant market pressure for the development of new, mechanism-based MAO-B inhibitors with more favorable pharmacokinetic profiles. Results: An innovative approach was developed for the drug design which involves joining of the scaffolds with propargylamine core which is present in commercial drugs which target MAO enzymes. A more favorable thermodynamic profile was obtained for the newly designed N-methyl-Npropargyl-2-indol (42Me) using methods of script based molecular docking and molecular dynamics simulations. A more optimal kinetic profile of the inhibitory activity of the 42Me was characterized via the DFT mechanistic calculation on the MAO-B cluster-model. The population analysis affirmed the mechanism of hydride abstraction in the first step of the inhibtion reaction. Conclusion: Obtained results show that newly designed 42Me is kinetically and thermodynamically more favourable propargylamine inhibitor (MAOI) than known drugs, selegiline and rasagiline. MAO-B inhibition reaction with 42Me is 69x more efficacious than selegiline, or 622x more efficacious than rasagiline. Applied propargylamine MAOI design approach was proved succesful and acquired results will assist in the development of the new inhibitors with better kinetic and thermodynamic parameters