The compound has histamine H 1 receptor antagonist activity [ 5 ]. Histamine receptor H 1 is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. H 1 receptor antagonists are used as antiallergy drugs. Some histamine antagonists in which imidazole ring of the ligand is replaced with a bulky aromatic ring such as doxepin [ 6 ] display H 1 receptor antagonist activity, indicating that this ligand site appears to decide the affinity toward the histamine receptor subtypes.
Matrix metalloproteinases MMPs are calcium- and zinc-containing endopeptidases that have diverse roles in cell behaviors including cell proliferation, migration, and differentiation. Inhibitors of some MMP subtypes had been reported for anticancer activity.
The second-generation MMP inhibitors such as batimastat 8 have a more potent inhibitory activity than that of the first-generation MMP inhibitors such as marimastat 9.
Figure 2B , but their selectivity against MMP subtypes is insufficient. The pyridine ring of prinomastat appears to behave as a bioisostere of the benzene ring. AD is the most common cause of dementia. Its cause has been unclear. A breakthrough was made through the genetic study of some familial AD FAD patients with a mutation of the gene encoding amyloid precursor protein APP or presenilin gene.
They have an acidic optimum pH. They were designed on the basis of an inhibitor design approach as well as other aspartic proteases such as renin and human immunodeficiency virus protease [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ].
In , Sinha et al. We have also reported a series of peptidomimetic BACE1 inhibitors possessing a norstatine-type transition-state analog, phenyl norstatine Pns: 2R , 3S aminohydroxyphenylbutyric acid , at the P 1 position as shown in Figure 4 [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Peptidomimetic BACE1 inhibitor with a norstatine-type substrate transition-state analog. The inhibitors formulated by Elan and MSD researchers, compounds 16 and 17 , respectively, are shown in Figure 5.
Because the distance between the flap domain and the cleft domain that form the S 2 pocket of BACE1 is narrow, a planar aromatic ring such as an isophthalic scaffold can closely dock in the S 2 pocket of BACE1. A docking simulation study between inhibitor 18 and BACE1 revealed that the P 3 -phenyl group of inhibitor 18 , which interacts with the S 3 sub-pocket, adopts a folding structure against the P 2 -isophthalic scaffold.
We envisioned and designed an inhibitor that possessed a folding structure and synthesized inhibitor This compound featured a five-membered ring, oxazolidine, at the P 3 position in order to fix the folding pose between the P 2 -phenyl group and P 3 -isophthalic scaffold. Our premise was that the oxazolidine ring fixes the direction of the phenyl ring at the P 3 position, so the P 3 -phenyl ring might be able to bind closely to the S 3 sub-pocket of BACE1.
Next, we focused on a proton of the P 2 -isophthalic ring of inhibitor We demonstrated van der Waals repulsion between the proton on the isophthalic ring at the P 2 position and the five-membered ring at the P 3 position in inhibitor 19 docked at the active site of BACE1.
We focused on the steric-hindered interaction between the P 3 -phenyl group and a proton on the P 2 -isophthalic ring of a virtual inhibitor Figure 6 , which seemed to restrict its configuration. We calculated the steric energies in the respective conformers around the bond of the P 3 amide and P 2 -isophthalic ring of the virtual inhibitors as shown in Figure 6. Using an approach based on a conformer of the docked inhibitor in BACE1 the in silico conformational structure-based design [ 39 , 41 ], we adopted a pyridinedicarboxylic scaffold as a P 2 moiety, which lacked a proton from the isophthalic ring.
A docking simulation demonstrated that inhibitor 20 could adopt a stable folding structure having the same dihedral angle between the P 3 -amide and P 2 -isophthalic ring to the conformer docked in BACE1. There is room for further optimization of these inhibitors. In-silico conformational structure-based design of BACE1 inhibitor possessing a pyridine scaffold at the P 2 position. The P 2 moiety of the inhibitor interacts with the Arg side chain of BACE1 by hydrogen bonding in the crystal structure.
We compared the publicly available X-ray crystal structures of BACE1-inhibitor complexes and discovered that most inhibitors did not interact with Arg by hydrogen bonding [ 41 ]. The P 2 moieties in many crystal structures that interact with the BACE1-Arg side chain are a methyl group, carbonyl oxygen atom, or aromatic ring. The only exception was the interaction in the first reported X-ray crystal structure, 1FKN.
However, the hydrogen-bonding interaction between most of the inhibitors and the BACE1-Arg side chain was not shown in their crystal structures. It is likely that the researchers designed an inhibitor that possessed an N -methyl- N -methanesulfonyl group at the P 2 position in anticipation of the hydrogen-bonding interaction between the sulfonyl oxygen atom and the BACE1-Arg side chain.
As many researchers have designed BACE1 inhibitors with a hydrogen bond receptor on the basis of the first reported crystal structure 1FKN, docking models using 1FKN will require further review. The guanidino planes of BACE1-Arg in the crystal structures of most BACE1 complexes showed similar distances from the P 2 regions of the inhibitors regardless of their molecular size.
This potentially posed a serious issue for a docking simulation for the drug discovery of BACE1 inhibitors. In silico drug discovery using a docking simulation between a target biomolecule and drugs has provided important information. However, the software programs recognize arginine Arg as one of the charged amino acids, and the quantum chemical interactions involving an Arg side chain are unlikely to yield a reasonable output.
Crowley et al. Among them, the interactions between an Arg and a Tyr were found to be the most abundant. Average rating 4.
Vote count: 7. No votes so far! Be the first to rate this page. Tell us how we can improve this page in your own language if you prefer? Close Animation controls: Display controls:. Tutorial - Pyridine - Nucleophilic catalysis. NOTE: Important charges and non-bonding electrons are shown throughout the animation except during the transition phase Click the structures and reaction arrows to view the 3D models and animations respectively Pyridine is a reasonable nucleophile for carbonyl groups and is often used as a catalyst in acylation reactions.
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