Multistep Modeling Strategy To Improve the Binding Affinity Prediction of PET Tracers to Aβ42: Case Study with Styrylbenzoxazole Derivatives.
Positron emission tomography (PET) tracers play an important role in the diagnosis of Alzheimer's disease, a condition that leads to progressive dementia and memory loss. A high binding affinity and specificity of the PET tracers to amyloid oligomers and fibrils are crucial for their successful application as diagnostic agents. In this sense, it is essential to design PET tracers with enhanced binding affinities, which can lead to more precise and earlier detection of Alzheimer's disease conditions. The application of in silico methodology for the design and development of efficient PET tracers may serve as an important route to improved Alzheimer's disease diagnosis. In this work, the performance of widely used computational methods is explored for predicting experimental binding affinities of styrylbenzoxazole (SB) derivatives against a common amyloid protofibril. By performing docking, molecular dynamics, and quantum chemistry calculations in sequence their combined predictive performance is explored. The present work emphasizes the merits as well as limitations of these simulation strategies in the realm of designing PET tracers for Alzheimer's disease diagnosis.
Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology , SE-10691 Stockholm, Sweden.
Kanagasabai
K
Balamurugan
Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology , SE-10691 Stockholm, Sweden.
Natarajan Arul
NA
Murugan
Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology , SE-10691 Stockholm, Sweden.
Hans
H
Ågren
D000544:Alzheimer Disease / Q000000981:diagnostic imaging; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001583:Benzoxazoles / Q000737:chemistry*; D015195:Drug Design; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010446:Peptide Fragments / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011789:Quantum Theory; D019275:Radiopharmaceuticals / Q000737:chemistry; D013343:Styrenes / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D001583:Benzoxazoles; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D013343:Styrenes; C075222:amyloid beta-protein (1-42)
Alzheimer’s disease; PET tracers; amyloid-β peptide; density functional theory; molecular dynamics