Investigation of the Binding Affinities of Novel Aryl-Aminopyridine-Peptide Conjugates as Potential Therapeutics Against Cancer Proteins

Abstract

Targeted cancer therapy has revolutionized modern oncology by enabling selective inhibition of molecular drivers responsible for uncontrolled proliferation, metastasis, and therapeutic resistance. In the present study, a novel class of aryl-aminopyridine-peptide conjugates was investigated as potential multi-target anticancer candidates against three clinically relevant proteins: Bcr-Abl kinase for chronic myelogenous leukemia (K562 model), cyclin-dependent kinase-2 (CDK2) for cervical carcinoma (HeLa model), and epidermal growth factor receptor (EGFR) for Fem-x melanoma-associated proliferation pathways. The designed hybrid molecules incorporated a 2-amino-4-arylpyridine pharmacophore tethered through a Gly-Gly linker to the cancer-targeting peptide sequence RWQWRWQWR. Molecular docking studies revealed favorable binding energies ranging from −9.1 to −12.4 kcal/mol across the selected targets, with strong hydrogen bonding, π–π stacking, electrostatic contacts, and hydrophobic stabilization within catalytic pockets. Molecular dynamics simulations performed for 200 ns confirmed excellent conformational stability of the docked complexes, showing RMSD equilibration below 2.5 Å and persistent intermolecular interactions. MM-PBSA calculations further supported stable complex formation with negative binding free energies. ADMET screening predicted acceptable pharmacokinetic behavior, low hepatotoxicity risk, and moderate oral bioavailability. The integrated results suggest that aryl-aminopyridine-peptide conjugates may serve as promising lead structures for the development of selective anticancer therapeutics targeting hematological and solid tumors simultaneously.