Sandbox southuniversity6 - Revision history

Arthur Cox at 00:24, 30 June 2012

Arthur Cox — Sat, 30 Jun 2012 00:24:53 GMT

←Older revision		Revision as of 00:24, 30 June 2012
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	==Medicinal Chemistry of HIV Integrase Inhibitors==		==Medicinal Chemistry of HIV Integrase Inhibitors==

-	When AIDS was first discovered in the 1980s, an individual's prognosis was grim, with a life expectancy on the order of 10 years. With development of effective antiviral drugs, this has increased up to 50 years or more. The HIV virus encodes several enzymes that are drug targets. The first effective drugs that were developed inhibit [[reverse transcriptase]]. The next drugs that were developed inhibit another ~~enzymes~~ that the virus encodes, [[HIV protease]]. The drugs that are under consideration here, the [[HIV integrase]] inhibitors are the most recently available class. Using multiple classes of drugs in combination has turned out to be a vital factor in effective treatment of HIV infection. For this reason, new integrase inhibitors have been avidly pursued by medicinal chemists across the globe.	+	When AIDS was first discovered in the 1980s, an individual's prognosis was grim, with a life expectancy on the order of 10 years. With development of effective antiviral drugs, this has increased up to 50 years or more. The HIV virus encodes several enzymes that are drug targets. The first effective drugs that were developed inhibit [[reverse transcriptase]]. The next drugs that were developed inhibit another enzyme that the virus encodes, [[HIV protease]]. The drugs that are under consideration here, the [[HIV integrase]] inhibitors are the most recently available class. Using multiple classes of drugs in combination has turned out to be a vital factor in effective treatment of HIV infection. For this reason, new integrase inhibitors have been avidly pursued by medicinal chemists across the globe.

-	Some of the first experimental compounds ~~that were~~ developed were members of a class called β-diketo acids~~, since there are~~ 2 carbonyl groups beta to each other, with one of them alpha to a carboxylic acid functional group. Although they are referred to as "diketo acids (DKAs)", in solution they can also exist as the tautomeric enols. This is important, since it is the enol tautomer that is proposed to ~~be species that~~ actually ~~binds~~ to the integrase enzyme.	+	Some of the first experimental compounds developed were members of a class called β-diketo acids. These compounds have 2 carbonyl groups beta to each other, with one of them alpha to a carboxylic acid functional group. Although they are referred to as "diketo acids (DKAs)", in solution they can also exist as the tautomeric enols. This is important, since it is the enol tautomer that is proposed to actually bind to the integrase enzyme.

Arthur Cox at 00:19, 30 June 2012

Arthur Cox — Sat, 30 Jun 2012 00:19:11 GMT

←Older revision		Revision as of 00:19, 30 June 2012
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	. The viral and host DNA are also shown		. The viral and host DNA are also shown

		+	<scene name='Sandbox_southuniversity6/Initial_view/1'>TextToBeDisplayed</scene>
		+	<scene name='Sandbox_southuniversity6/Initial_view_zoom1/1'>TextToBeDisplayed</scene>

	</StructureSection>		</StructureSection>
		+
		+


	<references/>		<references/>

Arthur Cox at 20:02, 29 June 2012

Arthur Cox — Fri, 29 Jun 2012 20:02:24 GMT

←Older revision		Revision as of 20:02, 29 June 2012
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	The structure to the right is the first HIV integrase inhibitor approved in the US, raltegravir (Isentress). Compare its structure to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule, with hydrogen bond donor, acceptor, and donor functional groups In the same orientation as they are in the DKA?		The structure to the right is the first HIV integrase inhibitor approved in the US, raltegravir (Isentress). Compare its structure to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule, with hydrogen bond donor, acceptor, and donor functional groups In the same orientation as they are in the DKA?

-	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>Compare the 3D structure at the right to that of the 2D depiction above. Note the 4-fluoro phenyl group, the hydrogen bond donor, and the 2 hydrogen bond acceptors that are part of the pharmacophore.	+	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>Compare the 3D structure at the right to that of the 2D depiction above. Note the 4-fluoro phenyl group, the hydrogen bond donor, and the 2 hydrogen bond acceptors that are part of the pharmacophore.<ref>PMID:8703075</ref>

	HIV integrase is the enzyme that is responsible for inserting viral DNA into host (human) DNA. The next interactive structure shows raltegravir <scene name='Sandbox_southuniversity6/3oya_trim/1'>bound to a viral integrase enzyme</scene>		HIV integrase is the enzyme that is responsible for inserting viral DNA into host (human) DNA. The next interactive structure shows raltegravir <scene name='Sandbox_southuniversity6/3oya_trim/1'>bound to a viral integrase enzyme</scene>
	. The viral and host DNA are also shown		. The viral and host DNA are also shown
-


	</StructureSection>		</StructureSection>
		+
		+
		+	<references/>

Arthur Cox at 18:46, 29 June 2012

Arthur Cox — Fri, 29 Jun 2012 18:46:31 GMT

←Older revision		Revision as of 18:46, 29 June 2012
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	The functional groups proposed for the [[pharmacophore]] of the DKAs includes a aromatic ring located a certain distance from a group of hydrogen bond donating and accepting groups. The orientation of a hydrogen bond donor group relative to 2 required hydrogen bond acceptors is very important for activity.		The functional groups proposed for the [[pharmacophore]] of the DKAs includes a aromatic ring located a certain distance from a group of hydrogen bond donating and accepting groups. The orientation of a hydrogen bond donor group relative to 2 required hydrogen bond acceptors is very important for activity.

-
-	<quiz display=simple>
-	{Looking at the enol tautomer of L-731,988, how many hydrogen bond donors do you see?
-	\|type="()"}
-	+ 3
-	- 1
-	- 2
-	</quiz>

	<quiz display=simple>		<quiz display=simple>
Line 33:		Line 25:

	[[Image:isentress_view2.png\|left\|200px\|raltegravir (isentress)]]		[[Image:isentress_view2.png\|left\|200px\|raltegravir (isentress)]]
-	The structure to the right is the first HIV integrase inhibitor approved in the US, raltegravir (Isentress). Compare its structure to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule, with hydrogen bond donor, acceptor, and donor functional groups ~~next to each other~~?	+	The structure to the right is the first HIV integrase inhibitor approved in the US, raltegravir (Isentress). Compare its structure to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule, with hydrogen bond donor, acceptor, and donor functional groups In the same orientation as they are in the DKA?

	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>Compare the 3D structure at the right to that of the 2D depiction above. Note the 4-fluoro phenyl group, the hydrogen bond donor, and the 2 hydrogen bond acceptors that are part of the pharmacophore.		<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>Compare the 3D structure at the right to that of the 2D depiction above. Note the 4-fluoro phenyl group, the hydrogen bond donor, and the 2 hydrogen bond acceptors that are part of the pharmacophore.

-	HIV integrase is the enzyme that is responsible for inserting viral DNA into host (human) DNA. The next interactive structure shows raltegravir bound to a viral integrase enzyme. The viral and host DNA are also shown	+	HIV integrase is the enzyme that is responsible for inserting viral DNA into host (human) DNA. The next interactive structure shows raltegravir <scene name='Sandbox_southuniversity6/3oya_trim/1'>bound to a viral integrase enzyme</scene>
		+	. The viral and host DNA are also shown

-	<scene name='Sandbox_southuniversity6/3oya_trim/1'>TextToBeDisplayed</scene>


	</StructureSection>		</StructureSection>

Arthur Cox at 15:21, 5 June 2012

Arthur Cox — Tue, 05 Jun 2012 15:21:54 GMT

←Older revision		Revision as of 15:21, 5 June 2012
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	The structure to the right is the first HIV integrase inhibitor approved in the US, raltegravir (Isentress). Compare its structure to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule, with hydrogen bond donor, acceptor, and donor functional groups next to each other?		The structure to the right is the first HIV integrase inhibitor approved in the US, raltegravir (Isentress). Compare its structure to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule, with hydrogen bond donor, acceptor, and donor functional groups next to each other?

-	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>~~The presence~~ of a hydrogen bond .	+	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>Compare the 3D structure at the right to that of the 2D depiction above. Note the 4-fluoro phenyl group, the hydrogen bond donor, and the 2 hydrogen bond acceptors that are part of the pharmacophore.
		+
		+	HIV integrase is the enzyme that is responsible for inserting viral DNA into host (human) DNA. The next interactive structure shows raltegravir bound to a viral integrase enzyme. The viral and host DNA are also shown
		+
		+	<scene name='Sandbox_southuniversity6/3oya_trim/1'>TextToBeDisplayed</scene>
		+
		+
	</StructureSection>		</StructureSection>

Arthur Cox at 01:35, 5 June 2012

Arthur Cox — Tue, 05 Jun 2012 01:35:07 GMT

←Older revision		Revision as of 01:35, 5 June 2012
Line 3:		Line 3:
	When AIDS was first discovered in the 1980s, an individual's prognosis was grim, with a life expectancy on the order of 10 years. With development of effective antiviral drugs, this has increased up to 50 years or more. The HIV virus encodes several enzymes that are drug targets. The first effective drugs that were developed inhibit [[reverse transcriptase]]. The next drugs that were developed inhibit another enzymes that the virus encodes, [[HIV protease]]. The drugs that are under consideration here, the [[HIV integrase]] inhibitors are the most recently available class. Using multiple classes of drugs in combination has turned out to be a vital factor in effective treatment of HIV infection. For this reason, new integrase inhibitors have been avidly pursued by medicinal chemists across the globe.		When AIDS was first discovered in the 1980s, an individual's prognosis was grim, with a life expectancy on the order of 10 years. With development of effective antiviral drugs, this has increased up to 50 years or more. The HIV virus encodes several enzymes that are drug targets. The first effective drugs that were developed inhibit [[reverse transcriptase]]. The next drugs that were developed inhibit another enzymes that the virus encodes, [[HIV protease]]. The drugs that are under consideration here, the [[HIV integrase]] inhibitors are the most recently available class. Using multiple classes of drugs in combination has turned out to be a vital factor in effective treatment of HIV infection. For this reason, new integrase inhibitors have been avidly pursued by medicinal chemists across the globe.

-	Some of the first experimental compounds that were developed were members of a class called β-diketo acids, since there are 2 carbonyl groups ~~located~~ beta to a carboxylic acid functional group. Although they are referred to as "diketo acids (DKAs)", in solution they can also exist as the tautomeric enols. This is important, since it is the enol tautomer that is proposed to be species that actually binds to the integrase enzyme.	+	Some of the first experimental compounds that were developed were members of a class called β-diketo acids, since there are 2 carbonyl groups beta to each other, with one of them alpha to a carboxylic acid functional group. Although they are referred to as "diketo acids (DKAs)", in solution they can also exist as the tautomeric enols. This is important, since it is the enol tautomer that is proposed to be species that actually binds to the integrase enzyme.

Arthur Cox at 23:41, 4 June 2012

Arthur Cox — Mon, 04 Jun 2012 23:41:46 GMT

←Older revision		Revision as of 23:41, 4 June 2012
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	[[Image:l731988_keto_enol.png\|left\|500px\|keto-enol tautomerism of L-731,988 a beta-diketo acid integrase inhibitor]]		[[Image:l731988_keto_enol.png\|left\|500px\|keto-enol tautomerism of L-731,988 a beta-diketo acid integrase inhibitor]]

-	The functional groups proposed for the [[pharmacophore]] of the DKAs includes a aromatic ring located a certain distance from hydrogen bond donating and accepting groups. ~~Looking at the enol tautomer~~ of ~~L-731,988, how many~~ hydrogen bond ~~donors do you see?~~	+	The functional groups proposed for the [[pharmacophore]] of the DKAs includes a aromatic ring located a certain distance from a group of hydrogen bond donating and accepting groups. The orientation of a hydrogen bond donor group relative to 2 required hydrogen bond acceptors is very important for activity.


-	~~[[Image:isentress.png\|left\|300px\|raltegravir (isentress)]]~~	+	<quiz display=simple>
-	~~Compare~~ the ~~structure~~ of ~~raltegravir (Isentress)to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule~~, ~~with~~ hydrogen bond ~~donor, acceptor, and donor functional groups next to each other~~?	+	{Looking at the enol tautomer of L-731,988, how many hydrogen bond donors do you see?
		+	\|type="()"}
		+	+ 3
		+	- 1
		+	- 2
		+	</quiz>

-	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>The ~~structure to the left is the first HIV integrase that has made it's way to market, raltegravir (Isentress)~~.	+	<quiz display=simple>
		+	{Looking at the enol tautomer of L-731,988, how many hydrogen bond donors do you see?
		+	\|type="()"}
		+	+ 3
		+	\|\| That is correct.
		+	- Distractor.
		+	\|\| Feedback for distractor.
		+	- Distractor.
		+	\|\| Feedback for distractor.
		+	- Distractor.
		+	\|\| Feedback for distractor.
		+	</quiz>
		+
		+	[[Image:isentress_view2.png\|left\|200px\|raltegravir (isentress)]]
		+	The structure to the right is the first HIV integrase inhibitor approved in the US, raltegravir (Isentress). Compare its structure to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule, with hydrogen bond donor, acceptor, and donor functional groups next to each other?
		+
		+	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>The presence of a hydrogen bond .
	</StructureSection>		</StructureSection>

Arthur Cox at 22:19, 4 June 2012

Arthur Cox — Mon, 04 Jun 2012 22:19:54 GMT

←Older revision		Revision as of 22:19, 4 June 2012
Line 10:		Line 10:
	The functional groups proposed for the [[pharmacophore]] of the DKAs includes a aromatic ring located a certain distance from hydrogen bond donating and accepting groups. Looking at the enol tautomer of L-731,988, how many hydrogen bond donors do you see?		The functional groups proposed for the [[pharmacophore]] of the DKAs includes a aromatic ring located a certain distance from hydrogen bond donating and accepting groups. Looking at the enol tautomer of L-731,988, how many hydrogen bond donors do you see?

		+
		+	[[Image:isentress.png\|left\|300px\|raltegravir (isentress)]]
		+	Compare the structure of raltegravir (Isentress)to that of the prototype DKA shown above. Can you see a hydrophobic group at one end of the molecule, with hydrogen bond donor, acceptor, and donor functional groups next to each other?

	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>The structure to the left is the first HIV integrase that has made it's way to market, raltegravir (Isentress).		<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>The structure to the left is the first HIV integrase that has made it's way to market, raltegravir (Isentress).
	</StructureSection>		</StructureSection>

Arthur Cox at 19:45, 1 June 2012

Arthur Cox — Fri, 01 Jun 2012 19:45:13 GMT

←Older revision		Revision as of 19:45, 1 June 2012
Line 3:		Line 3:
	When AIDS was first discovered in the 1980s, an individual's prognosis was grim, with a life expectancy on the order of 10 years. With development of effective antiviral drugs, this has increased up to 50 years or more. The HIV virus encodes several enzymes that are drug targets. The first effective drugs that were developed inhibit [[reverse transcriptase]]. The next drugs that were developed inhibit another enzymes that the virus encodes, [[HIV protease]]. The drugs that are under consideration here, the [[HIV integrase]] inhibitors are the most recently available class. Using multiple classes of drugs in combination has turned out to be a vital factor in effective treatment of HIV infection. For this reason, new integrase inhibitors have been avidly pursued by medicinal chemists across the globe.		When AIDS was first discovered in the 1980s, an individual's prognosis was grim, with a life expectancy on the order of 10 years. With development of effective antiviral drugs, this has increased up to 50 years or more. The HIV virus encodes several enzymes that are drug targets. The first effective drugs that were developed inhibit [[reverse transcriptase]]. The next drugs that were developed inhibit another enzymes that the virus encodes, [[HIV protease]]. The drugs that are under consideration here, the [[HIV integrase]] inhibitors are the most recently available class. Using multiple classes of drugs in combination has turned out to be a vital factor in effective treatment of HIV infection. For this reason, new integrase inhibitors have been avidly pursued by medicinal chemists across the globe.

-	Some of the first experimental compounds that were developed were members of a class called β-diketo acids, since there are 2 carbonyl groups located beta to a carboxylic acid functional group. Although they are referred to as "diketo acids", in solution they can also exist as the tautomeric enols.	+	Some of the first experimental compounds that were developed were members of a class called β-diketo acids, since there are 2 carbonyl groups located beta to a carboxylic acid functional group. Although they are referred to as "diketo acids (DKAs)", in solution they can also exist as the tautomeric enols. This is important, since it is the enol tautomer that is proposed to be species that actually binds to the integrase enzyme.


-	[[Image:l731988_keto_enol.png\|left\|500px\|keto-enol tautomerism of beta-~~keto acids~~]]	+	[[Image:l731988_keto_enol.png\|left\|500px\|keto-enol tautomerism of L-731,988 a beta-diketo acid integrase inhibitor]]
-		+

		+	The functional groups proposed for the [[pharmacophore]] of the DKAs includes a aromatic ring located a certain distance from hydrogen bond donating and accepting groups. Looking at the enol tautomer of L-731,988, how many hydrogen bond donors do you see?


	<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>The structure to the left is the first HIV integrase that has made it's way to market, raltegravir (Isentress).		<StructureSection load='RLT' size='500' side='right' caption='Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry [[RLT]])' scene=''>The structure to the left is the first HIV integrase that has made it's way to market, raltegravir (Isentress).
	</StructureSection>		</StructureSection>

Arthur Cox at 19:30, 1 June 2012

Arthur Cox — Fri, 01 Jun 2012 19:30:37 GMT

←Older revision		Revision as of 19:30, 1 June 2012
Line 1:		Line 1:
	==Medicinal Chemistry of HIV Integrase Inhibitors==		==Medicinal Chemistry of HIV Integrase Inhibitors==

-	When AIDS was first discovered in the 1980s, an individual's prognosis was grim, with a life expectancy on the order of 10 years. With development of effective antiviral drugs, this has increased up to 50 years. The HIV virus encodes several enzymes that are drug targets. The first effective drugs that were developed inhibit [[reverse transcriptase]].	+	When AIDS was first discovered in the 1980s, an individual's prognosis was grim, with a life expectancy on the order of 10 years. With development of effective antiviral drugs, this has increased up to 50 years or more. The HIV virus encodes several enzymes that are drug targets. The first effective drugs that were developed inhibit [[reverse transcriptase]]. The next drugs that were developed inhibit another enzymes that the virus encodes, [[HIV protease]]. The drugs that are under consideration here, the [[HIV integrase]] inhibitors are the most recently available class. Using multiple classes of drugs in combination has turned out to be a vital factor in effective treatment of HIV infection. For this reason, new integrase inhibitors have been avidly pursued by medicinal chemists across the globe.
		+
		+	Some of the first experimental compounds that were developed were members of a class called β-diketo acids, since there are 2 carbonyl groups located beta to a carboxylic acid functional group. Although they are referred to as "diketo acids", in solution they can also exist as the tautomeric enols.
		+
		+
		+	[[Image:l731988_keto_enol.png\|left\|500px\|keto-enol tautomerism of beta-keto acids]]
		+