Title:Molecular Modeling Study of Methylxanthines and Tannins as
Β-Secretase Inhibitors
Volume: 12
Issue: 3
Author(s): Lenir Cabral Correia, Jaderson Vieira Ferreira, Carlos Henrique Tomich de Paula da Silva, Carlton Anthony Taft and Lorane Izabel da Silva Hage-Melim*
Affiliation:
- Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá,
Macapá, Amapá, Brazil
Keywords:
Alzheimer's disease, Paullinia cupana, molecular docking, BACE-1, inhibitors, cognitive functions.
Abstract:
Background: Alzheimer’s disease (AD) has been characterized by a progressive
loss of cognitive functions, especially memory, impacting the daily life and personality of
the elderly. In the present study, we performed molecular modeling of methylxanthines and
tannins, with pharmacologic actions as stimulants of the Central Nervous System (CNS)
and antioxidant, respectively, present in Paullinia cupana Kunth (guarana), evaluating the
theoretical viability of these molecules as an alternative for the treatment of Alzheimer's
disease, specifically to act by inhibiting the β-secretase enzyme (BACE-1).
Methods: It has been accomplished optimization of selected chemical structures, derivation
of the pharmacophore, docking simulation, as well as prediction of physicochemical,
pharmacokinetic (ADME) and toxicological (TOX) properties, ending with the activity
prediction and synthetic viability of the selected molecules. For the physicochemical properties,
evaluated according to Lipinski’s Rule of Five, only methylxanthines, catechin and
epicatechin remained within the parameters evaluated.
Results: In the molecular docking, caffeine, theobromine, theophylline, catechin, epicatechin,
and proanthocyanidin, respectively, interacted with 57.14%, 42.86%, 28.57%,
57.14%, 28.57% e 57.14% of the active site amino acid residues of BACE-1. The ADME
properties indicated the average permeability of the blood-brain barrier to the molecules
caffeine, theobromine, theophylline, catechin and epicatechin, and caffeine, theobromine
and theophylline showed high intestinal absorption and low aggregation to plasma proteins.
The TOX properties showed only proanthocyanidin as a safer molecule. Only catechin
and epicatechin were related to the action of BACE-1 in predicting activity. The synthetic
viability of methylxanthine has been evaluated as high, while catechin and epicatechin
were median and proanthocyanidin has been evaluated as difficult.
Conclusion: Catechin and epicatechin tannins presented more favorable results indicating
the interaction of suppression of the Aβ aggregation, potential BACE-1 inhibitors.
