Mesothelioma, a malignant cancer affecting the pleura, peritoneum, and other organs, remains a major health challenge due to its poor prognosis. Proteins like Bcl-2A1 and Bcl2-L-10-2 contribute to apoptotic resistance, while NPM2 and CLDN-4 serve as potential biomarkers and therapeutic targets. This study used in silico methods to analyze these proteins, aiming to uncover molecular insights for targeted treatments. Using FASTA sequences from NCBI and PDB, 3D models were developed via homology modeling with Modeller 10.4 and validated using SAVES v6.0 and ProSA. Active site predictions with CASTp revealed five potential binding pockets per protein. Docking studies with Alimta and Bevacizumab identified key amino acids involved in drug interactions: LEU105, GLN23, and PHE43 in Bcl-2A1; ARG38, GLY23, and TYR17 in Bcl2-L-10-2; ARG12, TRP15, and GLY30 in NPM2; and VAL132, GLY163, and LEU73 in CLDN-4. These findings highlight crucial molecular targets, offering insights for developing more effective mesothelioma therapies.