Computational Analysis of SMPD1 Mutants and Their Binding Affinity with Desipramine: A Therapeutic Insight into Niemann–Pick Disease Type A

Abstract Niemann–Pick disease type A (NPD‐A) is a severe metabolic disorder caused by the deficiency of acid sphingomyelinase (ASM) due to mutations in the SMPD1 gene. The objective of this study was to identify and characterize the most deleterious SMPD1 mutations using a computational pipeline. A total of 177 mutations retrieved from public databases were evaluated based on pathogenicity, protein stability, biophysical properties, conservation analysis, and phenotypic relevance. Among these, two mutations, D253H and Y539H emerged as the most potentially pathogenic, causing significant disruption in protein function and stability. To further understand the structural implications, molecular docking was performed using desipramine as the ligand. The docking scores were − 4.63 kcal/mol for the native structure and − 6.16 kcal/mol and − 6.30 kcal/mol for D253H and Y539H, respectively, indicating for the mutants. Molecular dynamics (MD) simulations were then carried out, revealing improved structural stability, compactness, hydrogen bonding (H‐bond), and flexibility in the mutant complexes. Principal component analysis (PCA) and MM‐PBSA calculations demonstrated reduced conformational fluctuations and stronger binding energies in all desipramine‐bound complexes. These findings contribute valuable insights into the pathogenic mechanisms of SMPD1 mutations in NPD‐A offer potential leads for future therapeutic interventions targeting ASM dysfunction.