Causal-inferring and molecular-docking yield new targets for malignant melanoma therapy

Abstract

To obtain the causal related genes through Mendelian randomization and to screen the therapeutic drugs for malignant melanoma. Using Mendelian randomization, the causal relationship between genes and melanoma patients was calculated based on clumped genetic instruments extracted from genome-wide association studies. Prognostic significance of potential target genes was evaluated using survival information of patients with skin cutaneous melanoma in The Cancer Genome Atlas. In the Comparative Toxicogenomics Database (CTDbase), therapeutic drugs acting on target genes were screened amongst the interactions of medical and experimental evidence. Finally, considering the absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics of drugs, available drugs and their transformation structures are generated. The binding ability of receptor-ligand was evaluated by the molecular docking of target gene crystal structure with drug-like chemicals. As a result, three potential target genes LYZ, C1QB and BTN3A2, were negatively associated with melanoma patients, and showed significant difference (Logrank P value < 0.05) in overall survival and/or progression-free interval. A total of 183 unique interactive drug-like chemicals from CTDbase were obtained by the keywords of target genes. Through assessment of ADMET properties and binding ability of receptor-ligand, 15 antagonists and 25 agonists of matched drug-like chemicals showed therapeutic effects on target genes. On the basis of causal relationship, docking score and ADMET evaluation, these hit targets and drug-like compounds yield new directions for the development of potent therapeutic agents in melanoma patients.