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=Atorvastatin=
=Atorvastatin=
Atorvastatin, commercially known as Lipitor is a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA Reductase) inhibitor that works primarily in the liver<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>. It is part of a class of medications known as statins that are cholesterol-lowering medications<ref>Phizer Inc. "Lipitor." Lipitor: Atorvastatin Calcium Tablets. Phizer Inc., 2011. Web. 09 Mar. 2011. <http://www.lipitor.com/aboutLipitor.aspx>.</ref>. HMG-CoA reductase catalyzes the committed step in cholesterol synthesis, so by inhibiting this step, low density lipoprotein (LDL) cholesterol can be effectively lowered as well as increasing high density lipoprotein (HDL) levels. By lowering LDL, the likelihood of stroke and heart attack can be decreased<ref>NIH. "Atorvastatin." PubMed Health. National Institutes of Health, 01 July 2010. Web. 09 Mar. 2011. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000009/>.</ref>.  
Atorvastatin, commercially known as Lipitor is a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA Reductase) inhibitor that works primarily in the liver<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>. It is part of a class of medications known as statins that are cholesterol-lowering medications<ref>Phizer Inc. "Lipitor." Lipitor: Atorvastatin Calcium Tablets. Phizer Inc., 2011. Web. 09 Mar. 2011. <http://www.lipitor.com/aboutLipitor.aspx>.</ref>. HMG-CoA reductase catalyzes the committed step in cholesterol synthesis, so by inhibiting this step, low density lipoprotein (LDL) cholesterol can be effectively lowered as well as increasing high density lipoprotein (HDL) levels. By lowering LDL, the likelihood of stroke and heart attack can be decreased particularly in patients with hypercholesterolemia, mixed dyslipidemia, and homozygous familial hypercholesterolemia<ref>NIH. "Atorvastatin." PubMed Health. National Institutes of Health, 01 July 2010. Web. 09 Mar. 2011. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000009/>.</ref>.  


Bruce Roth, a Phizer employee, first synthesized atorvastatin in 1985. In 2008 Lipitor was the top-selling pharmaceutical in the world with $12.4 billion in sales. However, Lipitor's US patent protection is scheduled to expire in June 2011<ref>^"Pfizer wins patent extension on cholesterol drug". Associated Press. 6 January 2009. http://www.nj.com/business/index.ssf/2009/01/pfizer_wins_patent_extension_o.html.</ref>.
Bruce Roth, a Phizer employee, first synthesized atorvastatin in 1985. In 2008 Lipitor was the top-selling pharmaceutical in the world with $12.4 billion in sales. However, Lipitor's US patent protection is scheduled to expire in June 2011<ref>^"Pfizer wins patent extension on cholesterol drug". Associated Press. 6 January 2009. http://www.nj.com/business/index.ssf/2009/01/pfizer_wins_patent_extension_o.html.</ref>.
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==Structure and Synthesis==
==Structure and Synthesis==
[[Image:Lipitor.jpg]]
[[Image:Lipitor.jpg|right|thumb| Comparison of HMG-CoA and Atorvastatin ]]


When synthesizing a statin, four properties need to be taken into consideration: high affinity for the HMG-CoA reductase active site, selective uptake into hepatic cells instead of non-hepatic cells, low endogenous inhibitory equivalents, and a relatively long half-life/duration of effect.  
When synthesizing a statin, four properties need to be taken into consideration: high affinity for the HMG-CoA reductase active site, selective uptake into hepatic cells instead of non-hepatic cells, low endogenous inhibitory equivalents, and a relatively long half-life/duration of effect.  
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Vitamin D actually lowers atorvastatin active metabolite concentrations<ref>Schwartz, JB (February 2009). "Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence". Clin Pharmacol Ther 85 (2): 198–203.</ref>. Interestingly, grapefruit juice in co-administration with atorvastatin increases atorvastatin's Cmax (rate of absorption) and AUC (extent of absorption) which can lead to adverse effects. Grapefruit juice is a known inhibitor of Cytochrome P450 3A4 (CYP3A4), which is involved in the deactivation of avtorvastatin for excretion from the body<ref>Kane, GC; Lipsky, JJ (September 2000). "Drug-grapefruit juice interactions". Mayo Clin Proc 75 (9): 933–42</ref>.
Vitamin D actually lowers atorvastatin active metabolite concentrations<ref>Schwartz, JB (February 2009). "Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence". Clin Pharmacol Ther 85 (2): 198–203.</ref>. Interestingly, grapefruit juice in co-administration with atorvastatin increases atorvastatin's Cmax (rate of absorption) and AUC (extent of absorption) which can lead to adverse effects. Grapefruit juice is a known inhibitor of Cytochrome P450 3A4 (CYP3A4), which is involved in the deactivation of avtorvastatin for excretion from the body<ref>Kane, GC; Lipsky, JJ (September 2000). "Drug-grapefruit juice interactions". Mayo Clin Proc 75 (9): 933–42</ref>.
===Administration and Cost===
Atorvastatin is an oral medication available in 10, 20, and 40 mg sizes, with average prices being $1.82, $2.82, and $3.40 respectively. The starting does is usually 10 mg daily, and blood LDL levels should be checked four weeks after starting because the maximal effects of atorvastatin can be at that time. <ref>Goshman, Lorna. "Perspective on Cholesterol Lowering Agents: Atorvastatin." Journal of the Pharmacy Society of Wisconsin (1998): 28-34. Print.</ref>
[[Image:Atorvastatin-lipitor.jpg]]


=Targets=
=Targets=
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==HMG-CoA Reductase==
==HMG-CoA Reductase==
<applet load='1dq9' size='350' frame='true' align='right' caption='Catalytic portion of HMG-CoA Reductase in complex with its substrate, HMG-CoA' />


HMG-CoA is an endoplasmic reticulum transmembrane glycoprotein. It is a tetramer and an NADPH-dependent enzyme. HMG-CoA reductase contains an N-terminal membrane domain and a C-terminal catalytic domain. The catalytic portion can be further subdivided into an N-domain (N-terminal), a large L-domain, and a small S-domain. The L-domain binds the substrate, and the S-domain binds NADP<ref>"Pfam: Family: HMG-CoA_red (PF00368)." Pfam: Home Page. Web. 10 Mar. 2011. <http://pfam.sanger.ac.uk/family?acc=PF00368>.</ref>.  
<applet load='1hwk' size='350' frame='true' align='left' caption='HMG-CoA Reductase in complex with Lipitor' />
 
===Structural Features===
HMG-CoA is an endoplasmic reticulum transmembrane glycoprotein. It is a tetramer and <scene name='Sandbox_55/Nadph/1'>NADPH-dependent</scene> (ligands with orange atoms) enzyme. HMG-CoA reductase contains a <scene name='Sandbox_55/N_terminus_to_c_terminus/1'>N-terminal membrane domain and a C-terminal catalytic domain</scene>. The catalytic portion can be further subdivided into an N-domain (N-terminal), a large L-domain, and a small S-domain. The L-domain binds the substrate, and the S-domain binds NADP<ref>"Pfam: Family: HMG-CoA_red (PF00368)." Pfam: Home Page. Web. 10 Mar. 2011. <http://pfam.sanger.ac.uk/family?acc=PF00368>.</ref>.  
 


===Mechanism of Action===
===Mechanism of Action===
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In the normal catalytic mechanism of converting HMG-CoA to mevalonate, the carboxyl group of hydroxymethylglutarate that is in ester linkage to the thiol of coenzyme A is reduced twice via NADPH to an aldehyde and then to an alcohol.
In the normal catalytic mechanism of converting HMG-CoA to mevalonate, the carboxyl group of hydroxymethylglutarate that is in ester linkage to the thiol of coenzyme A is reduced twice via NADPH to an aldehyde and then to an alcohol.


[[Image:HMGCR_mechanism.gif|left|thumb| HMG-CoA Reductase Mechanism ]]
[[Image:HMGCR_mechanism.gif|right|thumb| HMG-CoA Reductase Mechanism ]]


HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate in the cholesterol biosynthesis pathway. Atorvastatin selectively and competitively inhibits HMG-CoA reductase. The inhibition subsequently increases the expression of LDL receptors on hepatocytes, which increases LDL uptake by hepatocytes, therefore decreasing the LDL-cholesterol concentration in the blood. Atorvastatin also increases levels of HDL-cholesterol.<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>  
HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate in the cholesterol biosynthesis pathway. Atorvastatin selectively and competitively inhibits HMG-CoA reductase. The inhibition subsequently increases the expression of LDL receptors on hepatocytes, which increases LDL uptake by hepatocytes, therefore decreasing the LDL-cholesterol concentration in the blood. Atorvastatin also increases levels of HDL-cholesterol.<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>  
<applet load='1hwk' size='350' frame='true' align='right' caption='HMG-CoA Reductase in complex with Lipitor' />




===Active Site===
===Active Site===
The active sites of HMG-CoA reductase are located at the interface of the two monomers of a dimer. Each active site has a loop that folds over part of the binding pocket; the loop contains an unusual cis-peptide bond that is highly conserved. The loop folds over the active site when both substrates (HMG-CoA and NADPH) are bound to exclude solvent from the active site.


The <scene name='Sandbox_55/Four_active_sites_and_residues/1'>four active sites</scene> of HMG-CoA reductase are located at the interface of the two monomers of a
<scene name='Sandbox_55/Dimer/1'>dimer</scene> (represented by the ball and stick residues). Each active site has a loop that folds over part of the binding pocket; the loop contains an unusual cis-peptide bond that is highly conserved. The loop folds over the active site when both substrates (HMG-CoA and NADPH) are bound to exclude solvent from the active site. In this view of the <scene name='Sandbox_55/Hydrophobic_residues/1'>hydrophobic and hydrophilic regions</scene> of the enzyme (hydrophobic:gray), the active sites contain many hydrophobic residues, which would not have favorable energetics with solvent.


The HMG binding pocket is the site of catalysis for HMG-CoA reductase. Three residues are essential for catalysis, E559, D767, and K691. K691 is positioned only 2.7 angstroms from the HMG O2 carbonyl oxygen, and stabilizes the negative charge of the first intermediate. H866 also stabilizes the thiol group. It is also believed that the closeness of E559 and D767 increases the pKa of E559, which allows it to be a proton donor for the final reduction of mevaldehyde to mevalonate. The HMG-CoA is bound by a domain consisting of combination of <scene name='Sandbox_55/Secondary_structure/1'>secondary structures</scene>, a central alpha helix surrounded by a triangular set of walls of beta sheets and alpha helices.


When <scene name='HMG-CoA_Reductase/Statin_ator/7'>atorvastatin,</scene> binds, the cis loop forms polar interactions, Ser 684, Asp 690, Lys 691, Lys 692, as well as hydrogen bond interactions between Glu 559 and Asp 767 with the O5-hydroxyl of the statin. Van der Waals interactions between Leu 562, Val 683, Leu 853, Ala 856, and Leu 857 of HMG-CoA reductase and thehydrophobic ring structures of atorvastatin also contribute to binding. These interactions result in a Km for HMG-CoA of 4uM. This allows atorvastatin to outcompete HMG-CoA in binding to HMG-CoA reductase.<ref>Roitelman J, Olender EH, Bar-Nun S, Dunn WA Jr, Simoni RD. Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum. J Cell Biol. 1992 Jun;117(5):959-73.</ref>


==Dipeptidyl peptidase 4 and Aryl hydrocarbon receptor==
==Dipeptidyl peptidase 4 and Aryl hydrocarbon receptor==
Atorvastatin is also an inhibitor of dipeptidyl peptidase 4, although it has no pharmacological effects. Dipeptidyl peptidase 4 removes N-terminal didpeptides from polypeptides and plays a role in T-cell activation, amino acid transport and metabolism<ref>.LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>.  
Atorvastatin is also an inhibitor of dipeptidyl peptidase 4, although it has no pharmacological effects. Dipeptidyl peptidase 4 removes N-terminal didpeptides from polypeptides and plays a role in T-cell activation, amino acid transport and metabolism<ref>.LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>.  
<applet load='2bgr' size='350' frame='true' align='left' caption='Dipeptidyl peptidase 4' />
<applet load='2bgr' size='350' frame='true' align='right' caption='Dipeptidyl peptidase 4' />
 


Atorvastatin also is an agonist of aryl hydrocarbon receptor. Aryl hydrocarbon receptor is a ligand-activated transcriptional activator that binds to the promoter region of genes it activates. It specifically activates the expression of multiple phase I and II xenobiotic metabolizing enzyme genes (E.g. CYP3A4. Aryl hydrocarbon receptor also mediates the biochemical and toxic effects of halogenated aromatic hydrocarbons, cell-cycle regulation, and plays an important role in the development and maturation of tissues.<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>
Atorvastatin also is an agonist of aryl hydrocarbon receptor. Aryl hydrocarbon receptor is a ligand-activated transcriptional activator that binds to the promoter region of genes it activates. It specifically activates the expression of multiple phase I and II xenobiotic metabolizing enzyme genes (E.g. CYP3A4. Aryl hydrocarbon receptor also mediates the biochemical and toxic effects of halogenated aromatic hydrocarbons, cell-cycle regulation, and plays an important role in the development and maturation of tissues.<ref>LDL-C, Decreasing. "DrugBank: Atorvastatin (DB01076)." DrugBank: Welcome. Web. 09 Mar. 2011. <http://www.drugbank.ca/drugs/DB01076>.</ref>


==References==
=References=


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