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Medicinal Chemistry of HIV Integrase InhibitorsMedicinal 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.

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.

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 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.

Looking at the enol tautomer of L-731,988, how many hydrogen bond donors do you see?

	3
	Distractor.
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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 In the same orientation as they are in the DKA?

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 . The viral and host DNA are also shown

spinqualitylabelsall models Structure of the first HIV integrase inhibitor to market, raltegravir (PDB entry RLT) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image