Sandbox Reserved 895: Difference between revisions

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=== '''[2.2.2] Structural Interaction and Stereoselectivity''' ===

Zhang and colleagues determined the binding interactions between RPE65 and emixustat by looking at the protein-ligand complex under three different considerations. The three considerations were RPE65 with a racemic emixustat, RPE65 with pure (''R'')-emixustat and RPE65 with pure (''S'')-emixustat. With all three cases, residual maps showed the presence of bound palmitate in the active site with the carboxylate oxygen forming a monodentate coordinate bond with the iron ion. The hydroxyl moiety in emixustat interacted via a hydrogen bond with the hydroxyl moiety in Thr147 whereas the primary amine was involved in a polar interaction with the carboxylate groups of Glu148 as well as the bound palmitate ligand. Crystal structure that was obtained in the presence of the racemic mixture of emixustat showed that the electron density was consistent with exclusive binding of the (''R'')-isomer ('''Figure 1B''').

Zhang and colleagues determined the binding interactions between RPE65 and emixustat by looking at the protein-ligand complex under three different considerations. The three considerations were RPE65 with a racemic emixustat, RPE65 with pure (''R'')-emixustat and RPE65 with pure (''S'')-emixustat. With all three cases, residual maps showed the presence of bound palmitate in the active site with the carboxylate oxygen forming a monodentate coordinate bond with the iron ion. The hydroxyl moiety in emixustat interacted via a hydrogen bond with the hydroxyl moiety in Thr147 whereas the primary amine was involved in a polar interaction with the carboxylate groups of Glu148 as well as the bound palmitate ligand. Crystal structure that was obtained in the presence of the racemic mixture of emixustat showed that the electron density was consistent with exclusive binding of the (''R'')-isomer ('''Figure 1B'''). Using the pure (''R'')-isomer and the pure (''S'')-isomer as a follow up study to the experiment confirmed the stereoselectivity for the (''R'')-isomer of emixustat. Stereoselectivity was present because of the interaction between the hydroxyl moieties in the enantiomers. Looking at the electron density of the 3-amino-1-phenylpropan-1-ol moiety of (''R'')-emixustat showed that when the racemic mixture was used the binding was that of the (''R'')-isomer. This showed that (''R'')-emixustat had a higher binding affinity when compared to (''S'')-emixustat. The difference in binding affinity and potency was likely because of the less favorable polar interaction observed in the (''S'')-isomer. Bond lengths for the hydroxyl-Thr137 Oγ , amine-Glu148 Oε2 and amine-palmitate O1 interactions were 3.1, 3.2 and 2.8 angstroms for the (''S'')-isomer and 3, 2.7 and 2.6 angstroms for the (''R'')-isomer respectively ('''Figure 8''').

The difference in bond lengths also confirms the increase in binding affinity and potency of the (R)-isomer. These interactions can be seen in '''Figure 9''' . <ref> DOI 26075817 </ref>

= '''[3] Disease Implications, Medical Relevance and Current Drug Development''' =

== '''[3.1] Dry (atrophic) age related macular degeneration''' ==

Dry AMD represents the progressive neurodegenerative disorder that impact the specialize neurons within the central part of the retinal called the macula. The degeneration of choriocapillaires, hRPE and the neurosensory cells such as rods and cones photoreceptor can lead to sensory loss within the macula. Age-dependent accumulation of cytotoxic lipofuscin such as A2E within the hRPE can lead to irreversible damage in the retina. It is suggested that retinoid cycle modulation can help prevent the accumulation of lipofuscin in the hRPE. Since RPE65 is expressed exclusively within the hRPE cells, this makes RPE65 a potential for drug research and development as theoretically a drug targeting RPE65 would minimize off-target effects. RPE65 is responsible for the chemical conversion of all-trans-retinyl ester to 11-cis-retinol which is the rate limiting step, in the retinoid cycle. As such, modulating RPE65 would effectively modulate the entire retinoid cycle. <ref> DOI 19668560 </ref>

Although (''R'')-emixustat failed to show clinical outcomes due to significant pharmacokinetic and pharmacodynamic limitations, (''R'')-emixustat became a proof-of-concept for RPE65 inhibition as well as the basis for structure-based drug design for future RPE65 inhibitors. Using (''R'')-emixustat, researchers were able to develop a screening for other RPE65 inhibitors. As part of the drug discovery process, subsequent hit identification, hit to lead, lead optimization processes would be required to develop new line of RPE65 inhibitors. These processes would require the use of structure activity relationships as well as structural property relationships to overcome the shortfalls that emixustat presented.

== '''[3.2] Stargardt’s Disease''' ==

Drastic accumulation of lipofuscin in the hRPE is a hallmark sign of juvenile-onset macular dystrophy also known as Stargardt’s Disease. It is suggested that retinoid cycle modulation can help prevent the drastic accumulation of lipofuscin leading to the development of Stargardt’s Disease. Currently in the United States, the use of (R)-emixustat is being tested in phase III clinical trails. <ref> DOI 24056528 </ref>

= References =

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@@ Line 91: / Line 91: @@
 === '''[2.2.2] Structural Interaction and Stereoselectivity''' ===
-Zhang and colleagues determined the binding interactions between RPE65 and emixustat by looking at the protein-ligand complex under three different considerations. The three considerations were RPE65 with a racemic emixustat, RPE65 with pure (''R'')-emixustat and RPE65 with pure (''S'')-emixustat. With all three cases, residual maps showed the presence of bound palmitate in the active site with the carboxylate oxygen forming a monodentate coordinate bond with the iron ion. The hydroxyl moiety in emixustat interacted via a hydrogen bond with the hydroxyl moiety in Thr147 whereas the primary amine was involved in a polar interaction with the carboxylate groups of Glu148 as well as the bound palmitate ligand. Crystal structure that was obtained in the presence of the racemic mixture of emixustat showed that the electron density was consistent with exclusive binding of the (''R'')-isomer ('''Figure 1B''').
+Zhang and colleagues determined the binding interactions between RPE65 and emixustat by looking at the protein-ligand complex under three different considerations. The three considerations were RPE65 with a racemic emixustat, RPE65 with pure (''R'')-emixustat and RPE65 with pure (''S'')-emixustat. With all three cases, residual maps showed the presence of bound palmitate in the active site with the carboxylate oxygen forming a monodentate coordinate bond with the iron ion. The hydroxyl moiety in emixustat interacted via a hydrogen bond with the hydroxyl moiety in Thr147 whereas the primary amine was involved in a polar interaction with the carboxylate groups of Glu148 as well as the bound palmitate ligand. Crystal structure that was obtained in the presence of the racemic mixture of emixustat showed that the electron density was consistent with exclusive binding of the (''R'')-isomer ('''Figure 1B'''). Using the pure (''R'')-isomer and the pure (''S'')-isomer as a follow up study to the experiment confirmed the stereoselectivity for the (''R'')-isomer of emixustat. Stereoselectivity was present because of the interaction between the hydroxyl moieties in the enantiomers. Looking at the electron density of the 3-amino-1-phenylpropan-1-ol moiety of (''R'')-emixustat showed that when the racemic mixture was used the binding was that of the (''R'')-isomer. This showed that (''R'')-emixustat had a higher binding affinity when compared to (''S'')-emixustat. The difference in binding affinity and potency was likely because of the less favorable polar interaction observed in the (''S'')-isomer. Bond lengths for the hydroxyl-Thr137 Oγ , amine-Glu148 Oε2 and amine-palmitate O1 interactions were 3.1, 3.2 and 2.8 angstroms for the (''S'')-isomer and 3, 2.7 and 2.6 angstroms for the (''R'')-isomer respectively ('''Figure 8''').
+<Placeholder for Figure 8>
+The difference in bond lengths also confirms the increase in binding affinity and potency of the (R)-isomer. These interactions can be seen in '''Figure 9''' . <ref> DOI 26075817 </ref>
+[[Image:Figrue9_R_S_Emixustat_binding_pocket.jpg|thumb|center|512 px|alt=Figure 8ABCD: R and S Emixustat Binding Pocket| '''Figure 8:''' (''R'')-Emixustat and (''S'')-Emixustat in RPE65 binding pocket <ref> DOI 26075817 </ref>]]
+= '''[3] Disease Implications, Medical Relevance and Current Drug Development''' =
+== '''[3.1] Dry (atrophic) age related macular degeneration''' ==
+Dry AMD represents the progressive neurodegenerative disorder that impact the specialize neurons within the central part of the retinal called the macula. The degeneration of choriocapillaires, hRPE and the neurosensory cells such as rods and cones photoreceptor can lead to sensory loss within the macula. Age-dependent accumulation of cytotoxic lipofuscin such as A2E within the hRPE can lead to irreversible damage in the retina. It is suggested that retinoid cycle modulation can help prevent the accumulation of lipofuscin in the hRPE. Since RPE65 is expressed exclusively within the hRPE cells, this makes RPE65 a potential for drug research and development as theoretically a drug targeting RPE65 would minimize off-target effects. RPE65 is responsible for the chemical conversion of all-trans-retinyl ester to 11-cis-retinol which is the rate limiting step, in the retinoid cycle. As such, modulating RPE65 would effectively modulate the entire retinoid cycle. <ref> DOI 19668560 </ref>
+Although (''R'')-emixustat failed to show clinical outcomes due to significant pharmacokinetic and pharmacodynamic limitations, (''R'')-emixustat became a proof-of-concept for RPE65 inhibition as well as the basis for structure-based drug design for future RPE65 inhibitors. Using (''R'')-emixustat, researchers were able to develop a screening for other RPE65 inhibitors. As part of the drug discovery process, subsequent hit identification, hit to lead, lead optimization processes would be required to develop new line of RPE65 inhibitors. These processes would require the use of structure activity relationships as well as structural property relationships to overcome the shortfalls that emixustat presented.
+== '''[3.2] Stargardt’s Disease''' ==
+Drastic accumulation of lipofuscin in the hRPE is a hallmark sign of juvenile-onset macular dystrophy also known as Stargardt’s Disease. It is suggested that retinoid cycle modulation can help prevent the drastic accumulation of lipofuscin leading to the development of Stargardt’s Disease. Currently in the United States, the use of (R)-emixustat is being tested in phase III clinical trails. <ref> DOI 24056528 </ref>
 = References =
 <references/>