Virtual screening following rational drug design based approach for introducing new anti amyloid beta aggregation agent

Abstract

Amyloid β (Aβ) sheets aggregations is the main reason of Alzheimer disease. The interacting areas between monomers are residue number 38 to 42. Inhibition of interaction between Aβ molecules prevents plaque formation. In the present study, we have performed a high-throughput virtual screening among ZINC database and top 1000 hits were checked again regarding binding affinity by AutoDock software. Top 4 successive second step screening hits was considered for drug design purpose against aggregation site of Aβ molecules. The toxicity and pharmacological properties of new designed ligands was assessed by PROTOX and FAFdrugs3 webservers. Several steps of modifications performed in the structures of hit#1 and hit#2 and finally new designed ligand based on hit 1, 1-RD-3 (3-[(Z)-6-Hydroxy-4-{[5-(2-methoxyethyl)-6-methyltetrahydro-2H-pyran-2-yl]methyl}-1-methyl-3-hexenyloxy]tetrahydro-2H-pyran-4-ol) and a designed ligand based on hit 2, 2-RD-2 (6-(Hydroxymethyl)-4-{5-hydroxy-6-methyl-4-[(3-methylcyclohexyl)methyl]tetrahydro-2H-pyran-2-yloxy}tetrahydro-2H-pyran-2,3,5-triol) could successfully pass pharmacological filters. The LD50 of 37000 mg/kg for 1-RD-3 and 2000 mg/kg for 2-RD-2 indicates that the designed ligands can be considered as new candidates for anti Aβ aggregation to treat Alzheimer's disease. Interestingly, after performing several modification steps still a considerable binding affinity of-9.3 kcal/mol for 1-RD-3 and-9.8 kcal/mol for 2-RD-2 still remained. Theoretically, the new designed molecules can reduce the deposition of Aβ in the cerebral cortex and as the results the Alzheimer symptoms could be decreased.