227
the enzymatic binding site induced by mutations. Hasserodt et al. [90–92] proposed
previously a new type of more mobile aspartic protease inhibitors, amino-aldehyde
peptides, which adopted their form based on a non-covalent interaction of a tertiary
amine nitrogen with a carbonyl group, the so-called N···CO bond. However, the
calculations exhibited that the presence of water molecule W301 induced a systematic competition between formation/dissociation of the N···CO bond and the interaction network involving the structural water molecule. Probably, this competition
determined the poor inhibition activity of amino-aldehyde peptides [90] and might
be avoided by the proper design of non-peptidic cyclic hydrazino-urea derivatives.
Another way for the development of drugs using HIV-1 PR as target with minimizing the drug resistance effect of HIV-1 is an irreversible inhibition. It consists
in the chemical modification of the binding site of HIV-1 PR, in particular, at the
key Asp 25 and Asp25′ amino acid fragments resulted in the complete lost of catalytic activity. One possible way is to include the oxyrane ring in the potential drug
structures [93–95]. Kóňa [96] analyzed two possible mechanisms of the irreversible
inhibition of HIV-1 protease by epoxide inhibitors by means of ab initio (MP2) and
DFT (B3LYP, MPW1K and M05-2X) calculations. In the first version of the reaction mechanism, the water molecule participated in the reaction, but another mechanism with a direct proton transfer from the acid catalyst to the inhibitor was shown
to be more preferable. The structures (118 atoms) modeling both the local minima
and transition state were located at the DFT [B3LYP/6-31+G(d,p)] level of theory.
The activation energy was predicted to be ca. 15–21 kcal/mol. The process of irreversible inhibition exhibited significantly large negative reaction energy. The most
probable mechanisms of modifying the model inhibitor structure were discussed.
7.2.14 HIV-1 Integrase
HIV-1 integrase (IN) is the relatively new and highly promising target for developing anti-AIDS drugs [97–99]. Understanding the inhibition mechanism of known
inhibitors would make possible testing new perspective drug candidates using the
DFT methods. However, it is still not known how the enzyme binds the inhibitors or its substrate, viral DNA [100]. The active site of HIV-1 IN is characterized
by the dinuclear magnesium center, coordinated by carboxylate groups of three
amino acid. Therefore, the main aim of theoretical efforts for the future development of the HIV-1 IN inhibitors with novel scaffolds is to provide a suitable ligand
capable of chelating two Mg
2 +
ions [101]. Noteworthy, some efficient IN inhibitors exist in the multiple tautomeric forms [102], which were not studied in detail.
Even less was known about the tautomerism of the ligands in the binding site of
HIV-1 IN. The most stable tautomeric forms and rotamers for the known inhibitors of HIV-1 IN: α,γ-diketoacids (84), α,γ-diketotriazole (85), dihydroxypyrimidine carboxylate (86) and 4-quinolone-3-carboxylic acid (87) were calculated at the
B3LYP/6-311++G(d,p) level of theory by Liao and Nicklaus [100]. Next, for the
studied structures the chelating complexes with two magnesium ions in the moiety
7 Density Functional Theory Calculations of Enzyme–Inhibitor …
the enzymatic binding site induced by mutations. Hasserodt et al. [90–92] proposed
previously a new type of more mobile aspartic protease inhibitors, amino-aldehyde
peptides, which adopted their form based on a non-covalent interaction of a tertiary
amine nitrogen with a carbonyl group, the so-called N···CO bond. However, the
calculations exhibited that the presence of water molecule W301 induced a systematic competition between formation/dissociation of the N···CO bond and the interaction network involving the structural water molecule. Probably, this competition
determined the poor inhibition activity of amino-aldehyde peptides [90] and might
be avoided by the proper design of non-peptidic cyclic hydrazino-urea derivatives.
Another way for the development of drugs using HIV-1 PR as target with minimizing the drug resistance effect of HIV-1 is an irreversible inhibition. It consists
in the chemical modification of the binding site of HIV-1 PR, in particular, at the
key Asp 25 and Asp25′ amino acid fragments resulted in the complete lost of catalytic activity. One possible way is to include the oxyrane ring in the potential drug
structures [93–95]. Kóňa [96] analyzed two possible mechanisms of the irreversible
inhibition of HIV-1 protease by epoxide inhibitors by means of ab initio (MP2) and
DFT (B3LYP, MPW1K and M05-2X) calculations. In the first version of the reaction mechanism, the water molecule participated in the reaction, but another mechanism with a direct proton transfer from the acid catalyst to the inhibitor was shown
to be more preferable. The structures (118 atoms) modeling both the local minima
and transition state were located at the DFT [B3LYP/6-31+G(d,p)] level of theory.
The activation energy was predicted to be ca. 15–21 kcal/mol. The process of irreversible inhibition exhibited significantly large negative reaction energy. The most
probable mechanisms of modifying the model inhibitor structure were discussed.
7.2.14 HIV-1 Integrase
HIV-1 integrase (IN) is the relatively new and highly promising target for developing anti-AIDS drugs [97–99]. Understanding the inhibition mechanism of known
inhibitors would make possible testing new perspective drug candidates using the
DFT methods. However, it is still not known how the enzyme binds the inhibitors or its substrate, viral DNA [100]. The active site of HIV-1 IN is characterized
by the dinuclear magnesium center, coordinated by carboxylate groups of three
amino acid. Therefore, the main aim of theoretical efforts for the future development of the HIV-1 IN inhibitors with novel scaffolds is to provide a suitable ligand
capable of chelating two Mg
2 +
ions [101]. Noteworthy, some efficient IN inhibitors exist in the multiple tautomeric forms [102], which were not studied in detail.
Even less was known about the tautomerism of the ligands in the binding site of
HIV-1 IN. The most stable tautomeric forms and rotamers for the known inhibitors of HIV-1 IN: α,γ-diketoacids (84), α,γ-diketotriazole (85), dihydroxypyrimidine carboxylate (86) and 4-quinolone-3-carboxylic acid (87) were calculated at the
B3LYP/6-311++G(d,p) level of theory by Liao and Nicklaus [100]. Next, for the
studied structures the chelating complexes with two magnesium ions in the moiety
7 Density Functional Theory Calculations of Enzyme–Inhibitor …