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In Silico Study of the Anti-MYC Potential of Lanostane-Type Triterpenes
José A C Oliveira1, Jonatas M Negreiro1, Fátima M Nunes1
1Department of Organic and Inorganic Chemistry, Science Center, Federal University of Ceará, Fortaleza, CE 60455-760, Brazil.
Abstract:
One of the most investigated molecular targets for anticancer therapy is the proto-oncogene MYC, which is amplified and thus overexpressed in many types of cancer. Due to its structural characteristics, developing inhibitors for the target has proven to be challenging. In this study, the anti-MYC potential of lanostane-type triterpenes was investigated for the first time, using computational approaches that involved ensemble docking, prediction of structural properties and pharmacokinetic parameters, molecular dynamics (MD), and binding energy calculation using the molecular mechanics-generalized born surface area (MM-GBSA) method. The analysis of physicochemical properties, druglikeness, and pharmacokinetic parameters showed that ligands ganoderic acid E (I), ganoderlactone D (II), ganoderic acid Y (III), ganoderic acid Df (IV), lucidenic acid F (V), ganoderic acid XL4 (VI), mariesiic acid A (VII), and phellinol E (VIII) presented properties within the filter used. These eight ligands, in general, could interact with the molecular target favorably, with interaction energy values between -8.3 and -8.6 kcal mol-1. In MD, the results of RMSD, RMSF, radius of gyration, and hydrogen bonds of the complexes revealed that ligands I, IV, VI, and VII interacted satisfactorily with the protein during the simulations and assisted in its conformational and energetic stabilization. The binding energy calculation using the MM-GBSA method showed better results for the MYC-VII and MYC-I complexes (-44.98 and -41.96 kcal mol-1, respectively). These results support the hypothesis that such molecules can interact with MYC for a considerable period, which would be an essential condition for them to exert their inhibitory activity effectively.
Insights
Lanostane triterpenes show potential as anti-MYC agents for cancer therapy. Computational studies identified specific compounds that favorably interact with the MYC oncoprotein, suggesting a basis for developing new cancer treatments.
Area of Science:
- Biochemistry
- Computational Chemistry
- Pharmacology
Background:
- The proto-oncogene MYC is a key target in cancer therapy, but its challenging structure hinders inhibitor development.
- Lanostane-type triterpenes are explored for their potential anticancer properties.
Purpose of the Study:
- To investigate the anti-MYC potential of lanostane-type triterpenes using computational methods.
- To identify specific triterpenes with favorable interactions and drug-like properties for MYC inhibition.
Main Methods:
- Ensemble docking
- Pharmacokinetic parameter prediction
- Molecular dynamics (MD) simulations
- Molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations
Main Results:
- Eight lanostane triterpenes (ganoderic acid E, ganoderlactone D, ganoderic acid Y, ganoderic acid Df, lucidenic acid F, ganoderic acid XL4, mariesiic acid A, and phellinol E) exhibited favorable physicochemical and pharmacokinetic properties.
- Ligands I, IV, VI, and VII demonstrated stable interactions with MYC during MD simulations.
- MM-GBSA calculations indicated strong binding affinities for MYC-VII (-44.98 kcal mol⁻¹) and MYC-I (-41.96 kcal mol⁻¹).
Conclusions:
- Lanostane-type triterpenes, particularly mariesiic acid A (VII) and ganoderic acid E (I), show significant potential for inhibiting the MYC oncoprotein.
- These findings support the development of these compounds as novel therapeutic agents for MYC-driven cancers.
