Sandbox Reserved 817: Difference between revisions

Line 66:

[[Image:Inhibiteur4.jpg|right|300px|thumb|'''Figure 2 :''' Docking study on compound 4 bound to BACE1. The coordinates of BACE1 was taken from the crystal structure of 1FKN. The protein is shown in cartoon, while the important residues and ligand 4 are shown in stick model.'']]

In the past, major efforts in designing BACE1 inhibitors were focused on the transition state analogs such as hydroxyethylamines, hydroxyethylene, and tatine-based peptidomimetic inhibitors~~. Although a large number of potent peptidomimetic inhibitors have been discovered,~~ their relatively large sizes and excessive number of hydrogen-bond donors and acceptors ~~make~~ it difficult for them to penetrate the blood brain barrier. Therefore many researchers in both academia and industry are trying to identify drug-like small molecules as BACE1 inhibitors, which hold great hopes to have good pharmacokinetic (PK) profiles and are suitable for drug development.

In the past, major efforts in designing BACE1 inhibitors were focused on the transition state analogs such as hydroxyethylamines, hydroxyethylene, and tatine-based peptidomimetic inhibitors but their relatively large sizes and excessive number of hydrogen-bond donors and acceptors made it difficult for them to penetrate the blood brain barrier. Therefore the scientific community focused its effort elsewhere.

~~The compounds~~, 1-(2-(1H-indol-1-yl)ethyl)guanidine, showed weak inhibition activity towards BACE1, about 42% inhibition ratio at the ligand concentration of 100 μM in the fluorescence resonance energy transfer (FRET) assay system. These compound occupied the S1 pocket and the guanidine moiety formed key binding interactions with the two catalytic aspartic acids, <scene name='56/568015/32/1'>Asp32</scene> and <scene name='56/568015/Asp228/1'>Asp228</scene> (Figure 2).

One of the discovered compound, 1-(2-(1H-indol-1-yl)ethyl)guanidine showed weak inhibition activity towards BACE1 (about 42% inhibition ratio at the ligand concentration of 100 μM in the fluorescence resonance energy transfer (FRET) assay system). These compound occupied the S1 pocket and the guanidine moiety formed key binding interactions with the two catalytic aspartic acids, <scene name='56/568015/32/1'>Asp32</scene> and <scene name='56/568015/Asp228/1'>Asp228</scene> (Figure 2).

As ~~exemplified~~ in some known BACE1 inhibitors in which the guanidine group is usually acylated, a compound was designed by introducing a carbonyl group into the α-position of the guanidine moiety.

As shown in some known BACE1 inhibitors in which the guanidine group is usually acylated, a compound was designed by introducing a carbonyl group into the α-position of the guanidine moiety.

To further improve the activity of this series of indole acylguanidines toward BACE1, the predicted conformation of inhibitors was scrutinized in the binding site of BACE1. There is a large hydrophobic sub-site at the top of the guanidine moiety. A benzyl group extending from the terminus of the guanidine moiety could fill this sub-pocket and thereby potentially increase the binding affinity. Analogs were synthesized based on indole and ethyl bromoacetate.

Sandbox Reserved 817: Difference between revisions

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@@ Line 66: / Line 66: @@
 [[Image:Inhibiteur4.jpg|right|300px|thumb|'''Figure 2 :''' Docking study on compound 4 bound to BACE1. The coordinates of BACE1 was taken from the crystal structure of 1FKN. The protein is shown in cartoon, while the important residues and ligand 4 are shown in stick model.'']]
-In the past, major efforts in designing BACE1 inhibitors were focused on the transition state analogs such as hydroxyethylamines, hydroxyethylene, and tatine-based peptidomimetic inhibitors. Although a large number of potent peptidomimetic inhibitors have been discovered, their relatively large sizes and excessive number of hydrogen-bond donors and acceptors make it difficult for them to penetrate the blood brain barrier. Therefore many researchers in both academia and industry are trying to identify drug-like small molecules as BACE1 inhibitors, which hold great hopes to have good pharmacokinetic (PK) profiles and are suitable for drug development.
+In the past, major efforts in designing BACE1 inhibitors were focused on the transition state analogs such as hydroxyethylamines, hydroxyethylene, and tatine-based peptidomimetic inhibitors but their relatively large sizes and excessive number of hydrogen-bond donors and acceptors made it difficult for them to penetrate the blood brain barrier. Therefore the scientific community focused its effort elsewhere.
-The compounds, 1-(2-(1H-indol-1-yl)ethyl)guanidine, showed weak inhibition activity towards BACE1, about 42% inhibition ratio at the ligand concentration of 100 μM in the fluorescence resonance energy transfer (FRET) assay system. These compound occupied the S1 pocket and the guanidine moiety formed key binding interactions with the two catalytic aspartic acids, <scene name='56/568015/32/1'>Asp32</scene> and <scene name='56/568015/Asp228/1'>Asp228</scene> (Figure 2).
+One of the discovered compound, 1-(2-(1H-indol-1-yl)ethyl)guanidine showed weak inhibition activity towards BACE1 (about 42% inhibition ratio at the ligand concentration of 100 μM in the fluorescence resonance energy transfer (FRET) assay system). These compound occupied the S1 pocket and the guanidine moiety formed key binding interactions with the two catalytic aspartic acids, <scene name='56/568015/32/1'>Asp32</scene> and <scene name='56/568015/Asp228/1'>Asp228</scene> (Figure 2).
-As exemplified in some known BACE1 inhibitors in which the guanidine group is usually acylated, a compound was designed by introducing a carbonyl group into the α-position of the guanidine moiety.
+As shown in some known BACE1 inhibitors in which the guanidine group is usually acylated, a compound was designed by introducing a carbonyl group into the α-position of the guanidine moiety.
 To further improve the activity of this series of indole acylguanidines toward BACE1, the predicted conformation of inhibitors was scrutinized in the binding site of BACE1. There is a large hydrophobic sub-site at the top of the guanidine moiety. A benzyl group extending from the terminus of the guanidine moiety could fill this sub-pocket and thereby potentially increase the binding affinity. Analogs were synthesized based on indole and ethyl bromoacetate.