Integrative structural and functional analysis of nsSNPs in AP1S1, CERCAM, and SLC34A2 reveals novel therapeutic targets in lung adenocarcinoma.

Lung adenocarcinoma (LUAD), a leading type of non-small cell lung cancer, exhibits considerable molecular diversity due to genetic, epigenetic, and transcriptomic alterations, which affect tumour progression, treatment efficacy, and prognosis. This study systematically investigates non-synonymous single-nucleotide polymorphisms (nsSNPs) in potential biomarker genes AP1S1, CERCAM, and SLC34A2 using in silico approaches. Missense variants were obtained from Ensembl VEP (86 in AP1S1, 568 in CERCAM, 532 in SLC34A2) and assessed for their potential harm using SIFT, PolyPhen-2 (high damaging scores >0.85), and CADD (PHRED >30). FATHMM-CScape identified several high-confidence oncogenic mutations, while mCSM indicated stabilizing effects in most mutants (ΔΔG >0 kcal/mol), particularly in buried residues. AlphaFold structures were validated (Ramachandran favoured >92%), followed by homology modelling of mutants. Virtual screening of FDA-approved drugs identified Mitoxantrone (binding -10.4/-11.8 kcal/mol to AP1S1/CERCAM) and Rutin (-9.0 kcal/mol to SLC34A2), with significant hydrogen bonds (e.g., ASN135). MD simulations lasting 100 ns verified the stability of these complexes, indicating that AP1S1, CERCAM, and SLC34A2 could serve as potential biomarkers for LUAD. Additionally, Mitoxantrone and Rutin emerged as possible therapeutic candidates, necessitating further experimental validation. These findings elucidate the impact of mutations, contributing to precision oncology supporting these genes as potential LUAD biomarker candidates and suggesting Mitoxantrone and Rutin as promising compounds for further experimental evaluation.