In Silico Design of Novel <i>Artocarpus altilis</i>-Derived Compounds Targeting the c-Myc/Max Heterodimer

The transcription factor c-Myc plays a pivotal role in regulating cell proliferation, growth, apoptosis, metabolism, and differentiation; however, its overexpression is strongly linked to cancer. Due to its intrinsically disordered structure, c-Myc has been inherently challenging to target therapeutically. To exert its oncogenic effects, c-Myc must form a heterodimer with its binding partner Max, enabling DNA binding and transcriptional activation of target genes. Despite decades of research, developing effective c-Myc inhibitors remains challenging due to issues such as low potency and poor pharmacokinetics. Here, we investigate natural compounds derived from Artocarpus altilis as potential c-Myc inhibitors using computational methods. From screening 81 bioactive compounds, four candidates demonstrated stronger binding affinities to c-Myc than the reference drug Alisertib: Ellagic acid, Artonin M, Cycloaltilisin 7, and Broussoflavonol F. Molecular dynamics simulations showed Broussoflavonol F had exceptional stability and the most favorable MM-PBSA binding energy. Pharmacokinetic analysis suggested promising drug properties, though some toxicity risks were noted. These findings highlight Artocarpus altilis-derived compounds, particularly Broussoflavonol F, as promising c-Myc inhibitors. This study provides a foundation for experimental validation and optimization, offering new therapeutic potential against c-Myc-driven cancers. Received: 10 December 2024 | Revised: 26 February 2025 | Accepted: 23 April 2025 Conflicts of Interest The authors declare that they have no conflicts of interest to this work. Data Availability Statement The data that support this work are available upon reasonable request to the corresponding author. Author Contribution Statement Tomilola Victor Akingbade: Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration. Ayobami Fidelix: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Writing – original draft, Writing – review & editing, Supervision, Project administration. Jatin Jangra: Software, Investigation, Visualization. Olutola Adeyemo: Data curation, Writing – original draft, Writing – review & editing. Damilola Adeniyi: Validation, Data curation, Writing – original draft, Writing – review & editing. Dolapo Damilola Akinlose: Formal analysis, Resources, Writing – original draft, Writing – review & editing.