: Cancer is still a major cause of death in the world at the beginning of the- 21st century and remains a major focus for ongoing research and development. In recent years a promising approach to the therapeutic intervention of cancer has focused on antiangiogenesis therapies. This approach to intervening in cancer progression takes advantage of the idea that inhibiting or otherwise limiting the blood supply to tumors will deplete the tumor of oxygen and nutrients and will cause arrest of tumor cell growth and proliferation. This approach has been found to be effective and there are presently over 20 anti-angiogenic drugs undergoing various stages of evaluation in phase I, II or III clinical trials and numerous others in preclinical development. Vascular endothelial growth factor receptor 3 (VEGFR-3) supports tumor lymph angiogenesis. It was originally identified as a lymphangiogenic factor expressed in lymphatic endothelial cells. VEGFR-3 was detected in advanced human malignancies and correlated with poor prognosis. Previous studies show that activation of the VEGF-C/VEGFR-3 axis promotes cancer metastasis and is associated with clinical progression in patients with lung cancer, indicating that VEGFR-3 is a potential target for cancer therapy. By using a fast path planning approach, we then rapidly generated large amounts of flexible peptide conformations, allowing backbone and side chain flexibility. A newly introduced binding energy funnel ‘steepness score’ was applied for the evaluation of the protein–peptide-multi-ligand complexes binding affinity. KNIME-based BiogenetoligandorolTM - Pepcrawler simulations predicted high binding affinity for native protein–peptide-hyper-ligand complexes benchmark and low affinity for low-energy decoy complexes. As a result we managed finally to introduce an algorithm for high-resolution refinement and binding affinity estimation of novel designed inhibitors consisting of CGQMCTVWCSSGC conserved peptide substitution mimetic linked pharmaco-structures with potential antagonizing VEGFR-3-mediated oncogenic effects.