Alzheimer’s\nDisease Immunotherapy and Mimetic\nPeptide Design for Drug Development: Mutation Screening, Molecular\nDynamics, and a Quantum Biochemistry Approach Focusing on Aducanumab::Aβ2–7\nBinding Affinity

Seven treatments are approved for Alzheimer’s\ndisease, but\nfive of them only relieve symptoms and do not alter the course of\nthe disease. Aducanumab (Adu) and lecanemab are novel disease-modifying\nantiamyloid-β (Aβ) human monoclonal antibodies that specifically\ntarget the pathophysiology of Alzheimer’s disease (AD) and\nwere recently approved for its treatment. However, their administration\nis associated with serious side effects, and their use is limited\nto early stages of the disease. Therefore, drug discovery remains\nof great importance in AD research. To gain new insights into the\ndevelopment of novel drugs for Alzheimer’s disease, a combination\nof techniques was employed, including mutation screening, molecular\ndynamics, and quantum biochemistry. These were used to outline the\ninterfacial interactions of the Aducanumab::Aβ<sub>2–7</sub> complex. Our analysis identified critical stabilizing contacts,\nrevealing up to 40% variation in the affinity of the Adu chains for\nAβ<sub>2–7</sub> depending on the conformation outlined.\nRemarkably, two complementarity determining regions (CDRs) of the\nAdu heavy chain (HCDR3 and HCDR2) and one CDR of the Adu light chain\n(LCDR3) accounted for approximately 77% of the affinity of Adu for\nAβ<sub>2–7</sub>, confirming their critical role in epitope\nrecognition. A single mutation, originally reported to have the potential\nto increase the affinity of Adu for Aβ<sub>2–7</sub>,\nwas shown to decrease its structural stability without increasing\nthe overall binding affinity. Mimetic peptides that have the potential\nto inhibit Aβ aggregation were designed by using computational\noutcomes. Our results support the use of these peptides as promising\ndrugs with great potential as inhibitors of Aβ aggregation.