Abstract
Cyclobenzaprine (CBP) is a centrally acting muscle relaxant whose myriad of therapeutic applications imply the need of better understanding its pharmacokinetics and thermodynamics. Henceforth, this work was concerned with an in silico investigation of CBP main metabolizers in the human organism, namely CYP1A2 and CYP3A4. For this purpose, computational methods were employed, such as molecular docking and other semi-empirical approaches. Results evidenced that the model herein depicted for CBP-CYP1A2 may not reproducibly represent the physiological interaction between CBP and this enzyme. Moreover, CBP-CYP3A4 docking results evidence thermodynamic feasibility of the molecular docking model and were further corroborated by literature, what may reproducibly represent a possible interaction between CBP and this macromolecule.
Highlights
Cyclobenzaprine (CBP) is a centrally acting muscle relaxant whose applicability range from treating acute musculoskeletal pain to chronic conditions such as fibromyalgia
CBP metabolism is primarily mediated by P450family cytochromes (CYP), CYP1A2 and CYP3A4, what implies that the association of this muscle relaxant with other drugs primarily metabolized by these CYP isoforms might result in important interactions, which could affect patient safety
Results evidenced that CBP lowest energy conformer tricyclic ring does display a slight distortion in the vinyl moiety (Vin) towards the same plane of the terminal aliphatic chain (AC), which grants the molecule a bent shape (Figure 1A)
Summary
Cyclobenzaprine (CBP) is a centrally acting muscle relaxant whose applicability range from treating acute musculoskeletal pain to chronic conditions such as fibromyalgia. The structure of this compound is quite similar to that of tricyclic antidepressants, which implies the possibility of yet unknown therapeutic uses. In view of the importance of better understanding CBP metabolism as well as the thermodynamics of its docking with the major metabolizers (CYP1A2 and CYP3A4), this work is intended to employ cheminformatics tools to establish a semi-flexible docking model of CBP-CYP interaction. CBP structure had its energy minimized through molecular mechanic functions and was subjected to docking studies as a flexible ligand to interact with a rigid macromolecule i.e. CYP
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