Enzyme inhibitors human immunodeficiency virus protease

The viral protease enzyme, human immunodeficiency virus type 1 (HIV-1), is a causative agent of AIDS. HIV-1 mediates the processing of the viral precursor polyproteins. This process is essential for the production and maturation of infectious viruses [1,2]. CR1XIVAN is a specific and potent inhibitor of the HIV-1 protease, and is used in the treatment of AIDS. 

Chem., 39, 705 (1996). An Approach to Rapid Estimation of Relative Binding Affinities of Enzyme Inhibitors Application to Peptidomimetic Inhibitors of the Human Immunodeficiency Virus Type 1 Protease. 

Viswanadhan YN, Reddy MR, Wlodawer A, Varney MD, Weinstein JN. An approach to rapid estimation of relative binding affinities of enzyme inhibitors application to pep-tidomimetic inhibitors of the human immunodeficiency virus type 1 protease. J Med Chem 1996 39 705-712. 

FEP has been successfully used to calculate stability of mutant pro-teins, to examine solvation properties,and to predict relative free energies of enzyme—inhibitor binding in the human immunodeficiency virus 1 (HIV-1) protease system,... 

Indinavir sulfate is a protease inhibitor that inhibits human immunodeficiency virus (HIV) protease, the enzyme that cleaves viral polyprotein precursors into functional proteins in HIV-infected cells. Inhibition of this enzyme by indinavir results in formation of immature noninfectious viral particles. It is indicated in the treatment of HIV infection in combination with other antiretroviral agents. 

Ritonavir is an inhibitor of the human immunodeficiency virus (HIV) protease which, in combination with nucleoside analogs (600 mg/b.i.d. p.o.), is indicated in the treatment of HIV infection. Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor, which leads to production of noninfectious immature HIV particles. 

A key strategy in the treatment of acquired immunodeficiency syndrome (AIDS) has been to develop specific inhibitors that selectively block the actions of enzymes unique to the human immunodeficiency virus (HIV), which causes AIDS. Many laboratories are working on this approach to the development of therapeutic agents. Three key enzymes are current targets for AIDS therapy—reverse transcriptase, integrase, and protease. 

Hybrid potentials have been used to understand the mechanism of the human immunodeficiency virus (HIV) protease with the ultimate aim of being able to help in the design of inhibitors which could be useful as AIDS therapies. This enzyme, which catalyzes the hydrolysis of peptide bonds, is a homodimer. Its active center is at the interface of the two chains and consists of two catalytic aspartic acid residues from identical positions in each of the two chains. Although the aspartates are equivalent in the sequence, they are not equivalent when the substrate is present. It is known that when the enzyme is active one of the aspartic residues is protonated and it is thought that there is a lytic water molecule that is also involved in the catalysis. 

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