Multi-Target Computational Analysis of Monacolin X Against Angiogenesis-Associated Receptors

Breast cancer (BC) is a serious global health problem with increasing incidence and mortality, while current treatments are often associated with severe side effects and drug resistance. Therefore, new therapeutic agents with enhanced efficacy and minimal adverse effects are needed. Our previous study reported the anti-angiogenic effect of Monacolin X, a secondary metabolite of a marine-sponge-associated fungus, using combined in vitro, ex vivo, in vivo (including a DMBA-induced mammary carcinoma rat model) and in silico approaches, identifying VEGFR2 as its principal target. In this study, molecular docking and molecular dynamics (MD) simulations were performed to investigate the interactions between Monacolin X and key anti-angiogenic targets, including IGFR, EGFR, neuropilin 1 (NRP1), Tie-2, VEGFR1/2, and PDGFRα, using Schrödinger Glide XP. Selective inhibitors were used for comparison. Docking analysis showed significant binding affinities of Monacolin X toward IGFR (G-score = −9.05), PDGFRα (−7.57), VEGFR1 (−7.42), Tie-2 (−7.40), VEGFR2 (−7.515), EGFR (−6.80), and NRP1 (−5.15), with hydrogen bonding, hydrophobic contacts, and electrostatic interactions contributing to stable complexes. Notably, IGFR and Tie-2 exhibited strong interactions, suggesting potential inhibition of angiogenic signaling. MD simulations were performed for 50 ns at 300 K and 1 bar; complex stability was assessed using RMSD and RMSF analyses, and the persistence of key active site hydrogen bonds was quantified as a percentage of simulation frames. MM-PBSA binding free-energy calculations further supported the thermodynamic feasibility of these interactions. Overall, these findings highlight Monacolin X’s potential as an anti-angiogenic agent for BC. However, further in vitro and in vivo studies are required to validate its efficacy and clinical relevance.