Homology Models and Molecular Modeling of Human Retinoic Acid Metabolizing Enzymes Cytochrome P450 26A1 (CYP26A1) and P450 26B1 (CYP26B1)

Karlsson, MagnusÖrebro universitet,Akademin för naturvetenskap och teknik (författare)

Homology models of cytochrome P450 26A1 and cytochrome P450 26B1 were constructed using the crystal structures of human, CYP2C8, CYP2C9, and CYP3A4 as templates for the model building. The homology models generated were investigated for their docking capacities against the natural substrate all-trans-retinoic acid (atRA), ﬁve different tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and R115866. Interaction energies (IE) and linear interaction energies (LIE) were calculated for all inhibitors in both homology models after molecular dynamics (MD) simulation of the enzyme-ligand complexes. The results revealed that the homologues had the capacity to distinguish between strong and weak inhibitors. Important residues in the active site were identiﬁed from the CYP26A1/B1-atRA complexes. Residues involved in hydrophobic interactions with atRA were Pro113, Phe222, Phe299, Val370, Pro371, and Phe374 in CYP26A1 and Leu88, Pro118, Phe222, Phe295, Ile368, and Tyr272 in CYP26B1. Hydrogen bonding interactions were observed between the atRA carboxylate group and Arg 90 in CYP26A1 and with Arg76, Arg95, and Ser369 in CYP26B1.

Strid, ÅkeÖrebro universitet,Akademin för naturvetenskap och teknik(Swepub:oru)aesd (författare)
Sirsjö, AllanÖrebro universitet,Hälsoakademin(Swepub:oru)aso (författare)
Eriksson, Leif A.Örebro universitet,Akademin för naturvetenskap och teknik(Swepub:oru)lfen (författare)
Örebro universitetAkademin för naturvetenskap och teknik (creator_code:org_t)

Ingår i:Journal of Chemical Theory and ComputationColumbus, Ohio : American Chemical Society4:6, s. 1021-10271549-96181549-9626

Av författaren/redakt...: Karlsson, Magnus; Strid, Åke; Sirsjö, Allan; Eriksson, Leif A ...

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