Computational elucidation of the potential mechanisms of Warburgia ugandensis against colorectal cancer

Abstract

Colorectal cancer remains a major global health challenge due to its high incidence, mortality, therapeutic resistance, and treatment-related adverse effects. Warburgia ugandensis is a medicinal plant that has demonstrated anti-colorectal cancer; however, the specific bioactive compounds responsible and their underlying molecular mechanisms remain underexplored. This study investigated the anti-colorectal cancer potential and molecular mechanisms of W. ugandensis phytochemicals using an integrated computational approach. Phytochemicals were retrieved from published literature and the Collection of Open Natural Products database, standardized, and screened for drug-likeness and oral bioavailability. Potential protein targets were predicted and intersected with colorectal cancer-associated genes, followed by network pharmacology and functional enrichment analyses. Molecular docking, 100 ns molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area binding energy calculations, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses were performed to evaluate compound-target interactions, complex stability, and pharmacological properties. Among 242 identified phytochemicals, 21 compounds satisfied drug-likeness and oral bioavailability criteria. Target prediction identified 435 potential protein targets of the screened phytochemicals, of which 411 overlapped with colorectal cancer-associated genes. Network analysis of the overlapping targets identified PIK3CA, PIK3CD, GNAI1, GNAI3, and SRC as key hub genes. Functional enrichment analysis suggested that these targets are involved in cancer-relevant signaling pathways, including the phosphatidylinositol 3-kinase-protein kinase B, insulin receptor, and relaxin signaling pathways. Molecular docking identified quercetin, kaempferol, and bemadienolide as leading candidates, with strong binding affinities toward GNAI1 (-9.8 kcal/mol), GNAI3 (-9.6 kcal/mol), and PIK3CD (-8.7 kcal/mol), respectively. Molecular dynamics simulations demonstrated stable protein-ligand complexes with reduced structural fluctuations over 100 ns. Binding free energy analysis revealed favorable interactions, with quercetin-GNAI1 showing the strongest predicted binding stability (-86.2 ± 3.3 kcal/mol). Pharmacokinetic and toxicity predictions indicated high gastrointestinal absorption and generally low predicted toxicity profiles. This study provides computational, hypothesis-generating evidence that Warburgia ugandensis phytochemicals may modulate multiple molecular targets and signaling pathways involved in colorectal cancer. Quercetin, kaempferol, and bemadienolide represent promising candidates for further experimental investigation. Nevertheless, these predictive findings require validation through in-vitro and in-vivo studies to establish their therapeutic relevance. Not applicable.