Background:
Alzheimers Disease (AD) is a neurodegenerative disease which is characterized by
the deposition of amyloid plaques in the brain- a concept supported by most of the researchers worldwide. The
main component of the plaques being amyloid-beta (Aβ42) results from the sequential cleavage of Amyloid
precursor protein (APP) by beta and gamma secretase. This present study intends to inhibit the formation of
amyloid plaques by blocking the action of gamma secretase protein with Inhibitors (GSI).
Methods:
A number of Gamma Secretase Inhibitors (GSI) were targeted to the protein by molecular docking.
The inhibitor having the best affinity was used as a subject for further virtual screening methods to obtain
similar compounds. The generated compounds were docked again at the same docking site on the protein to
find a compound with higher affinity to inhibit the protein. The highlights of virtually screened compound
consisted of Pharmacophore Mapping of the docking site. These steps were followed by comparative assessments
for both the compounds, obtained from the two aforesaid docking studies, which included interaction
energy descriptors, ADMET profiling and PreADMET evaluations.
Results:
111 GSI classified as azepines, sulfonamides and peptide isosteres were used in the study. By molecular
docking an amorpholino-amide, compound (22), was identified to be the high affinity compound GSI
along with its better interaction profiles.The virtually screened pubchem compound AKOS001083915
(CID:24462213) shows the best affinity with gamma secretase. Collective Pharmacophore mapping (H bonds,
electrostatic profile, binding pattern and solvent accesibility) shows a stable interaction. The resulting ADMETand
Descriptor values were nearly equivalent.
Conclusion:
These compounds identified herein hold a potential as Gamma Secretase inhibitors.According to
PreADMET values the compound AKOS001083915 is effective and specific to the target protein. Its
BOILED-egg plot analysis infers the compound permeable to blood brain barrier.Comparative study for both
the compounds resulted in having nearly equivalent properties. These compounds have the capacity to inhibit
the protein which is indirectly responsible for the formation of amyloid plaques and can be further put to in
vitro pharmacokinetic and dynamic studies.