Discovery of Mitogen-Activated Protein Kinase for Melanoma Using Melphalan Based Hybrid Classic 3-Point Pharmacophore Virtual Screening and Molecular Docking Approach

Abstract

Melanoma, a highly aggressive type of skin cancer, poses a significant health risk due to its proclivity for metastasis and poor response to conventional treatments. Mutations in the MEPK are one of the key molecular alterations driving melanoma progression, resulting in constitutive activation of the MAP2K signaling pathway. Targeting this pathway, specifically the MAP2K, has emerged as a promising approach to melanoma treatment. This study investigates the therapeutic potential of Mitogen-activated protein kinase, which are compounds designed to inhibit the abnormal activity of mutated MEK, disrupting the oncogenic signaling cascade and stopping melanoma progression. The ChEMBL 2D database was used to conduct a comprehensive pharmacophore-based screening to identify potential mitogen-activated protein kinase with the desired molecular properties. Afterwards the initial screening, selected compounds underwent rigorous molecular docking studies to verify their binding affinity and interaction patterns with the MAP2K substance. Among the compounds tested, CHEMBL852 (Melphalan), CHEMBL250892(R)-Melphalan and CHEMBL1200863 (Metyrosine) had particularly high binding affinities, indicating potential efficacy as mitogen-activated protein kinase. Toxicity tests were carried out to assess the safety profiles of these compounds. Notably, metyrosine had a favorable toxicity profile across multiple endpoints, including hepatotoxicity, carcinogenicity, immunotoxicity, and cytotoxicity, indicating its potential as a safer therapeutic candidate. Metyrosine pharmacokinetics were further evaluated using ADME studies, which demonstrated its high water solubility and moderate lipophilicity, indicating favorable drug-like properties. These findings suggest that metyrosine may have higher bioavailability and fewer side effects than other potential inhibitors. Subsequently, this study identifies promising lead compounds, specifically metyrosineas, potential candidates for the research and development of novel mitogen-activated protein kinase for melanoma therapy. These compounds require additional experimental validation, optimization, and preclinical research to determine their therapeutic efficacy, safety, and potential for clinical application. This study highlights the importance of targeted therapies in the growing melanoma treatment landscape, paving the way for the development of novel strategies to combat this devastating disease.