Title

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

Authors

Garshasb Rigi^1*, Mohammad Vala Ashdar Nakhaei², Hoda Eidipour², Arshia Najimi², Fahimeh
Tajik², Niloufar Taher², Kamran Yarahmadi²

Affiliation

¹Department of Biology, Faculty of Science, Behbahan Khatam Alanbia University of Technology, Behbahan, Iran;

²Viravigene research institute, Tehran, Iran; Garshasb Rigi

Email

garshasbbiotech@gmail.com;

Article Type

Hypothesis

Date

Received January 17, 2016; Revised April 9, 2016; Accepted April 9, 2016; Published February 28, 2017

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-2Hpyran-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.

Keywords

Alzheimer,rational drug design, Amyloid β, Ligand, docking

Citation

Rigi et al. Bioinformation 13(2): 42-45 (2017)

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.