Background: Antibodies play a major role in the immunotherapy, basic researches and industrial processes. Studying interactions between antibody-antigen complexes is important to know how they function that helps to improve their properties and to design new better antibodies through rational engineering for therapeutic or biotechnological applications, including the production of biosensors. Nowadays, Antibody Engineering is widely used in many fields such as medicine, criminal sciences, military, defense industries, etc. Designing antibodies with desired properties are a challenging task. Computational docking is the method of predicting the conformation of a complex structure (such as antibody-antigen) from its separated elements. The validation of designed antibodies is carried out by docking tools. Materials and Methods: In this study, some potent nanobodies against death receptor5 (DR5) which had been selected using phage display technique, were modeled and docked with their antigen, then were mutated to improve their binding affinity. Based on the experimental results, docking structural prediction of DR5-VHH complex was used for designing and validation of VHHs with higher affinity for binding to DR5 receptor. Results: By analysis of the models, several mutants of nanobodies were designed, and their properties improved in a predictable manner especially for their binding ability to DR5. Conclusion: The designed nanobodies, considering their binding site on DR5, could be potential candidates to trigger apoptosis in various cancer cells.