In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of beta-amyloid plaques associated with Alzheimer's disease

Abstract

Background: Alzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by beta-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of beta-amyloid plaques.

Rationale: We previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases.

Conclusion: Molecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-pi, pi-pi interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional hydrophobic interaction between the 2-thiophene moiety of Compound A and Ile69. The involvement of one catalytic triad residue (His438) of butyrylcholinesterase with the 3'-hydroxy group on ring A increases the selectivity of Compound A. C-C bond rotation around ring A also stabilizes and enhances the interaction of Compound A with butyrylcholinesterase. Furthermore, the classical network of hydrogen bonding interactions as formed by the catalytic triad of butyrylcholinesterase is disturbed by Compound A. This study may open a new avenue for structure-based drug design for Alzheimer's disease by considering the 3D-pharmacophoric features of the complex responsible for discriminating these two closely-related cholinesterases.

Figure 1

3D View. Energy-minimized three dimensional (3D) structure and molecular surface representation of A) symbolic compound from set 3 and B) Compound A; R₁ = 2-thiophene moiety.

Figure 2

Chemical featurers used for MVD re-docking protocol. The chemical properties of bound ligands are shown A) DECA, Grey; Steric centers, Green; Hydrogen-bond acceptors, Blue; Positive charges and B) BCH, Grey, Steric centers, Green; Hydrogen-bond acceptors, Blue; Positive charges.

Figure 3

Graphical representations of RMSD values of top-ranked re-docked poses and superimposition of selected conformations. Re-docked poses of A) DECA and B) BCH in blue as compared to their bound crystallographic conformations in red (See also Table 1).

Figure 4

Evaluation of selected docking protocol. Atoms of bound and re-docked conformations are scaled according to their energy contributions. The green line denotes the electrostatic bond A) DECA - 4.341 Å (4.354 Å for re-docked pose) and B) BCH - 3.887 Å (3.879 Å for re-docked pose).

Figure 5

Five Predicted binding modes of Compound A. A) 1ACL and B) 1P0P. Rejected poses are represented as stick in red while selected pose is represented as color by element mode in stick.

Figure 6

Graphical representation of pair-wise Atom-Atom RMSD (Ǻ) (checking all automorphisms) of all 5 poses obtained. A) 1ACL and B) 1P0P.

Figure 7

Docked pose of Compound A in AChE. CT (Ser200, His440, Glu327; yellow), OH (Gly118, Gly119, Ala201; purple), AS (Trp84, Tyr121, Glu199, Gly449, Ile444; Grey), ABP (Trp233, Phe290, Phe292, Phe330, Phe331; Deep pink), PAS (Asp72, Tyr121, Ser122, Trp279, Phe331, Tyr334; Cyan) and Compound A (green) are represented as stick model. The hydrogen bonding (black dashed lines with bond lengths) by flexible orientation of ring A and molecular surface of Compound A shows how well it fits in the deep and narrow aromatic gorge lined with aromatic residues. The residues indicated as italic fonts in legend are considered as dual characteristics.

Figure 8

Role of aromatic amino acid residues. π-π interactions between the ring A of Compound A and aromatic side chains of Tyr334 and Phe331 (chartreuse). Residues are shown within 5.0 Å in the active site of AChE.

Figure 9

Docked pose of Compound A in BChE. CT (Ser198, His438, Glu325; yellow), OH (Gly116, Gly17, Ala199; purple), π-π interacting residues (Trp82, Tyr332; chartreuse) and charged residues (Glu197, Asp70; orange red) are shown here around the molecular surface representation of Compound A. The amino acid residues in grey are substituted in BChE.

Figure 10

Selection of best pose. Two top poses of Compound A are superimposed to justify the selection of correct posture that makes appropriate interactions with BChE. The rotation around C-C bond makes ring A more prone towards hydrogen bonding (see Results and Discussion).

Figure 11

RMSD plot. RMSD of the backbone atoms (Cα, N, C) of 1ACL complexed with Compound A with respect to the first snapshot as a function of time.

Figure 12

Movement of aromatic gorge. Width of the aromatic gorge as taken between the center of mass of Trp279 and Gly335. The increase and decrease in the width at different time intervals describes the behavior of aromatic gorge as distorted by Compound A.

Figure 13

Disturbance of catalytic triad. Involvement of hydrogen bonding interactions during the simulation time.

Figure 14

Breakage of hydrogen bonding interactions between Ser198 and His438.