Sandbox Reserved 817: Difference between revisions
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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. | 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. | ||
All the compounds tested by the BACE1 enzymatic inhibition assay at the concentration of 100 μM, and IC50 values were determined for compounds showing > 90% inhibition to the enzyme. The introduction of the simple benzyl group did not enhance the inhibitory activity. However, when a 3,5-dichlorobenyl group was introduced, the potency was improved. Surprisingly, a compound which has an acetamide group between two chlorine atoms showed a more substantial increase in potency. If two chlorine atoms are remplaced with two hydrogen atoms or reduced the amide to an amine, the resulting compounds displayed much weaker activities against BACE1. To characterize the binding mode of indole acylguanidines to BACE1, X-ray crystallography was used to determinate the bona fide conformation of ligands bound to the enzyme | All the compounds tested by the BACE1 enzymatic inhibition assay at the concentration of 100 μM, and IC50 values were determined for compounds showing > 90% inhibition to the enzyme. The introduction of the simple benzyl group did not enhance the inhibitory activity. However, when a 3,5-dichlorobenyl group was introduced, the potency was improved. Surprisingly, a compound which has an acetamide group between two chlorine atoms showed a more substantial increase in potency. If two chlorine atoms are remplaced with two hydrogen atoms or reduced the amide to an amine, the resulting compounds displayed much weaker activities against BACE1. To characterize the binding mode of indole acylguanidines to BACE1, X-ray crystallography was used to determinate the bona fide conformation of ligands bound to the enzyme | ||
The acylguanidine formed crucial interactions with two catalytic aspartic acids (<scene name='56/568015/Asp228/1'>Asp228</scene> and <scene name='56/568015/32/1'>Asp32</scene>) through three hydrogen bonds. The carboxyl oxygen atoms of the acylguanidine formed water-bridged hydrogen bonds with the side chains of <scene name='56/568015/Gln73/1'>Gln73d</scene> and <scene name='56/568015/Thr72/1'>Thr72</scene>, and a direct hydrogen bond with Gln73 as well. The substituted benzyl group occupied the S1 subsite of the substrate binding pocket of BACE1. The carboxyl oxygen atom of acetamide also forms a water-bridged hydrogen bond with the nitrogen atom of the amide group of Gln73, while the acetamide nitrogen atom forms another hydrogen bond directly with the main chain carboxyl oxygen of Phe108. The two chlorine atoms may force the acetamide group adopting a perpendicular angle with respect to the benzyl group, which plays an important role in binding interactions between acetamide and BACE1. Besides, the hydrogen bonds of the inhibitor with residues Gln73 and Thr72 induce a semi-closed conformation. Such a conformation of the flap further strengthens the ligand binding to the enzyme. The indole group pointed toward the back of the S1’ pocket forming a cation-πinteraction with Arg235, which appears to contribute further interactions to improve the potency of the inhibitor. <ref name="three">PMID:23681056</ref> | The acylguanidine formed crucial interactions with two catalytic aspartic acids (<scene name='56/568015/Asp228/1'>Asp228</scene> and <scene name='56/568015/32/1'>Asp32</scene>) through three hydrogen bonds. The carboxyl oxygen atoms of the acylguanidine formed water-bridged hydrogen bonds with the side chains of <scene name='56/568015/Gln73/1'>Gln73d</scene> and <scene name='56/568015/Thr72/1'>Thr72</scene>, and a direct hydrogen bond with <scene name='56/568015/Gln73/1'>Gln73d</scene> as well. The substituted benzyl group occupied the S1 subsite of the substrate binding pocket of BACE1. The carboxyl oxygen atom of acetamide also forms a water-bridged hydrogen bond with the nitrogen atom of the amide group of <scene name='56/568015/Gln73/1'>Gln73d</scene>, while the acetamide nitrogen atom forms another hydrogen bond directly with the main chain carboxyl oxygen of <scene name='56/568015/Phe108/1'>Phe108</scene>. The two chlorine atoms may force the acetamide group adopting a perpendicular angle with respect to the benzyl group, which plays an important role in binding interactions between acetamide and BACE1. Besides, the hydrogen bonds of the inhibitor with residues <scene name='56/568015/Gln73/1'>Gln73d</scene> and <scene name='56/568015/Thr72/1'>Thr72</scene> induce a semi-closed conformation. Such a conformation of the flap further strengthens the ligand binding to the enzyme. The indole group pointed toward the back of the S1’ pocket forming a cation-πinteraction with <scene name='56/568015/Arg235/1'>Arg235</scene>, which appears to contribute further interactions to improve the potency of the inhibitor. <ref name="three">PMID:23681056</ref> | ||
