Integrative genomic and biophysics analysis of MAPK1 rs1057519911 in cervical cancer: genetic association and therapeutic implications

Human papillomavirus (HPV) infection-related cervical cancer is mostly connected with dysregulated MAPK1 signaling, where genetic variations may alter protein function and affect treatment responses. This study examined the potential treatment implications of the oncogenic missense mutation rs1057519911 in the Mitogen-Activated Protein Kinase-1 (MAPK1) gene in relation to cervical cancer susceptibility. The Tetra-ARMS PCR method was used to genotype 300 participants, comprising 100 HPV-positive patients, 100 HPV-negative patients, and 100 healthy controls. The CT and TT genotypes of MAPK1 rs1057519911 were significantly linked with increased odds of cervical disease, mainly in HPV-positive patients (CT: OR = 15.77, 95% CI: 6.80-36.54; TT: OR = 180.95, 95% CI: 37.99–861.93; both P < 0.001). The T allele was also significantly linked with HPV-negative (OR = 8.73, 95% CI: 5.28–14.44) and HPV-positive disease (OR = 15.22, 95% CI: 9.10-25.46; both P < 0.001), supporting an association between the MAPK1 rs1057519911 variant and cervical disease, mostly HPV-positive disease. The rs1057519911 variant results in an E322K amino acid mutation in MAPK1, prompting further structural and dynamic analyses to evaluate its impact on inhibitor binding. Molecular docking analysis of literature-reported MAPK1 inhibitors against both the wild-type and E322K mutant proteins identified SCH772984 as the highest-affinity ligand for the mutant protein, showing a binding affinity of -9.7 kcal/mol compared with − 8.8 kcal/mol for the wild-type protein. Following 50 ns molecular dynamics simulations and post-MD analyses such as RMSD, RMSF, β-factor, radius of gyration, SASA, and dynamic cross-correlation, the findings showed that the mutant complex was more stable. Binding free energy calculations showed more favorable binding of SCH772984 to the MAPK1 E322K variant, with net binding energies of -73.18 kcal/mol (MM-GBSA) and − 76.72 kcal/mol (MM-PBSA), compared with − 66.22 and − 61.83 kcal/mol, respectively, for wild-type MAPK1. These results provide the first evidence linking MAPK1 rs1057519911 to cervical cancer susceptibility in the Khyber Pakhtunkhwa population and identify SCH772984 as a promising drug candidate for targeted therapy in HPV-associated cervical cancer.