Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1397718 | European Journal of Medicinal Chemistry | 2010 | 8 Pages |
Immunotherapy by cocaine-binding monoclonal antibodies (mAbs) has emerged as a promising strategy for the treatment of cocaine addiction. The human (γ1 heavy chain)/murine (λ light chain) chimeric mAb 2E2 has excellent affinity and specificity for cocaine and recent animal studies have demonstrated 2E2's ability in vivo to reduce cocaine levels in the brain as well as alter cocaine self-administration behavior in rats. In this study, we used mAb 2E2 amino acid sequence information to create a homology model for the 3-D structure of its Fv fragment. Subsequent computational docking studies revealed the intermolecular interactions potentially responsible for mAb 2E2's cocaine binding properties. The driving force of cocaine binding was identified as a combination of hydrophobic interactions and a single hydrogen bond between a light chain tyrosine residue and a carbonyl oxygen atom of cocaine. The model also allowed for an in silico evaluation of single/double residue mutations in the heavy and light chain variable regions that might further enhance mAb 2E2's cocaine binding properties.
Graphical abstractAfter determining its amino acid sequence, a homology model of a human/mouse anti-cocaine monoclonal antibody was developed. Subsequent computational docking studies provided a molecular-level characterization of protein/ligand interactions responsible for the antibody's cocaine affinity and specificity and demonstrate its potential as an immunotherapeutic agent.Figure optionsDownload full-size imageDownload as PowerPoint slide