While esketamine is an FDA-approved therapy for treatment-resistant depression, its broader clinical utility is often restricted by safety concerns, particularly psychotomimetic side effects, and suboptimal efficacy. To address this, we utilized computational chemistry to rationally design esketamine analogs in silico, specifically focusing on structural modifications that would optimize interactions at the Asn616 and Leu642 residues of the NMDAR. Our approach involved synthesizing these analogs computationally and then docking them into the NMDAR binding site using GOLD molecular docking software to assess their binding affinity and pose quality. The outcome of this study was the identification of specific analogs that demonstrated significantly improved binding affinity compared to the parent compound. Notably, "Analog 1" achieved a docking score of 44.974, surpassing Esketamine’s score of 37.618. Structural analysis revealed that reducing the hydrogen bond distance with Asn616 from 5.6 Angstroms to 4.1 Angstroms significantly improved affinity, while methylating the cyclohexanone ring at the C-5 position optimized hydrophobic interactions at Leu642. These findings established Analog 1 and Analog 3 as promising lead candidates for further alkylation and in vivo testing for neuropsychiatric treatments.