Comparative Binding Analysis of Monoclonal Antibodies Against Native and Mutant Type in ErbB2 Receptor: A Theoretical Modeling Approach

Author(s): R. Rajasekaran, Sethumadhavan Rao.

Journal Name: Current Pharmaceutical Biotechnology

Volume 10 , Issue 7 , 2009

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Abstract:

Trastuzumab and pertuzumab are monoclonal antibodies, used for inhibiting the ErbB2 receptor which is over expressed in breast and ovarian cancer. In this study, we identified that the most detrimental single point mutation is from tryptophan to cysteine at the residue position of 452 on ErbB2 receptor by using I-Mutant 2.0, SIFT and PolyPhen programs. The modeled mutant showed less stability than native ErbB2 protein based on both total energy of the mutant and stabilizing residues in the mutant protein. This is due to deviation between the mutant and native ErbB2 having the RMSD of about 2.83Å. Further, we found, pertuzumab showed a marginal higher binding affinity with ErbB2 receptor of native and mutant type with a binding free energy of -16.01 kcal/mole each as compared to trastuzumab, showing a binding free energy of -15.26 kcal/mole in ErbB2 of native type. On the contrary, trastuzumab showed a remarkably high binding affinity with ErbB2 receptor of mutant type having the binding free energy -24.40 kcal/mol. Moreover, the reason for high binding efficiency of trastuzumab with mutant ErbB2 is due to additional hydrogen bonding of amino acid Asn30 of trastuzumab with Asp596 and Glu598 of ErbB2 receptor of mutant type. Based on this work, we propose that pertuzumab could be the potential monoclonal antibody against ErbB2 for native type and trastuzumab could be the potential monoclonal antibody against ErbB2 of mutant type. Therefore combined administration of trastuzumab and pertuzumab could be a novel strategy for breast cancer treatment.

Keywords: Breast cancer, Point mutation, ErbB2 receptor, Monoclonal antibodies, Stability, Binding Energy, Intermolecular interactions

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Article Details

VOLUME: 10
ISSUE: 7
Year: 2009
Page: [701 - 708]
Pages: 8
DOI: 10.2174/138920109789542057
Price: $58

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