Network pharmacology, molecular docking, and dynamics simulation of 7-phenyl-5-(p-tolyl)pyrido[2,3-d] pyrimidine-4-amine as anticancer agents with multitarget inhibitory action

Abstract

Cancer remains a leading cause of morbidity and mortality worldwide, and the effectiveness of current therapeutic strategies is often limited by drug resistance, tumor heterogeneity, and suboptimal clinical responses. Consequently, multi-target drug design has gained increasing attention as a promising strategy to simultaneously modulate several interconnected pathways involved in tumor progression. In this context, the present study evaluated 7-phenyl-5-(p-tolyl)pyrido[2,3-d]pyrimidin-4-amine as a potential multitarget scaffold for anticancer drug discovery using an integrated computational framework. To explore its possible polypharmacological profile, network pharmacology was first applied to identify cancer-associated targets linked to the compound, after which four representative proteins involved in complementary oncogenic mechanisms, namely telomerase reverse transcriptase (TERT), murine double minute 2 (MDM2), epidermal growth factor receptor (EGFR), and cyclin-dependent kinase 2 (CDK2), were selected for further investigation. Subsequently, molecular docking was performed to predict ligand-target interactions, while 100 ns molecular dynamics simulations were conducted to assess the structural stability of the resulting complexes. In parallel, in silico ADMET analysis was used to evaluate the pharmacokinetic and toxicity profile of the compound. The docking results showed favorable predicted binding affinities across the selected targets, ranging from -8.1 to -9.7 kcal/mol, suggesting potential interactions with multiple cancer-related proteins. Consistently, molecular dynamics simulations supported the stability of the ligand-protein complexes during the simulation period, as reflected by RMSD, RMSF, radius of gyration, and hydrogen-bond analyses. Moreover, ADMET predictions indicated acceptable drug-like properties; however, toxicity alerts, including possible hepatotoxicity, neurotoxicity, blood-brain barrier penetration, and cytochrome P450 inhibition, highlight the need for further structural optimization. Overall, these findings suggest that this pyrido[2,3-d]pyrimidine derivative may represent a preliminary scaffold for multitarget anticancer investigation, although experimental validation remains essential to confirm its biological activity, tumor selectivity, safety, and therapeutic relevance.