A molecular model for cocaine binding by the immunotherapeutic human/mouse chimeric monoclonal antibody 2E2

作者：Lape Michael; Paula Stefan; Ball William J Jr^*

来源：European Journal of Medicinal Chemistry, 2010, 45(6): 2291-2298.

DOI：10.1016/j.ejmech.2010.02.004

• Homology modeling
• Drug addiction
• Immunotherapy
• Molecular docking
• Antibody
• Cocaine

Immunotherapy by cocaine-binding monoclonal antibodies (mAbs) has emerged as a promising strategy for the treatment of cocaine addiction. The human (gamma(1) heavy chain)/murine (lambda 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 F(v), 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 silica evaluation of single/double residue mutations in the heavy and light chain variable regions that might further enhance mAb 2E2's cocaine binding properties.

• 出版日期2010-6