Antibody therapeutics are designed against a target protein, and are increasingly being used in cancer therapy. High affinity and selectivity are critical issues for antibody therapeutic capacity. It is critical to be able to understand how certain amino acid substitutions will change the binding energy (affinity maturation). Docking algorithms have expanded into the protein–protein domain with current standards including ZDOCK, ClusPro, Haddock, RosettaDock and several others. Common to these methods are sampling techniques such as Monte Carlo or fast-Fourier transform, which aim to generate structural conformations that can be scored with a function which estimates the energetic favorability of two docked structures. Rational engineering methods can be applied with reasonable success to optimize physicochemical characteristics of antibody drugs.
CDR walking mutagenesis
Random mutagenesis by error-prone PCR
Various different mutagenesis strategies have proven useful to enhance the affinity of candidate therapeutic antibodies obtained by phage display. But it is practically unfeasible to generate all possible (combinations of) CDR residue mutants. The actual binding site usually involves multiple CDRs and exact mapping is a laborious task. Application of in silico analysis and prediction methods to antibody variable fragment (Fv) regions may be helpful. A set of algorithms, named affinity maturation after the similar process in B-cell response, attempts to determine if mutations or modifications to the binding partners have an impact on binding affinity or energetic favorability or generate mutations or sequences which increase the binding affinity of the partners.
In silico procedures
Dock at least the epitope fragment into the binding sites.
Combine theoretic and experimental information to make rational proposals.
Depends on the time you need to simulate and
the time required for the system to reach equilibrium.
Mature phage display platform.
Computer-guided homology modeling.
Conformational optimization methods.
Precise affinity evaluation.
Molecular docking and dynamics simulation methods.
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