Comparison of azacyclic urea A-98881 as HIV-1 protease inhibitor with cagedimeric N-benzyl 4-(4-methoxyphenyl)-1,4-dihydropyridine as representativeof a novel class of HIV-1 protease inhibitors: A molecular modeling study

The functional groups of cage dimeric N-alkyl substituted 3,5-bis(hydroxyme thyl)-4-(4-methoxyphenyl)-1,4-dihydropyridines are similar to those of cycl ic and azacyclic ureas that are potent inhibitors of HIV-1 protease of the dihydroxyethylene- and hydroxyethylene type, respectively. In the following study the conformity of common functional groups is investigated concernin g their orientation in space as well as in the enzyme HIV-1 protease. Start ing from X-ray crystal data of the centrosymmetric cage dimeric N-benzyl de rivative with ester groups, the derivative with hydroxymethylene groups was built and a systematic conformational search was per-formed for the confor mationally important torsion angles considering electrostatic and van der W aals interactions. From the huge number of conformations those comprising c entrosymmetrical and C-2-symmetrical energy minima were selected and minimi zed. The three remaining conformers were fitted to the azacyclic urea A-988 81 selected from the HIV-1 protease enzyme-inhibitor complex using the cent roids of the corresponding aromatic residues and additionally by the field fit option of the Advanced CoMFA module of SYBYL. Interestingly, the energe tically most favourable one, which, additionally, possesses C-2-symmetry li ke the active site cavity of HIV-1 protease, showed the best fit. Comparing the electrostatic potential (EP) of the latter with the EP of A-98881 the aromatic residues show excellent accordance. Slight differences in the exte nt of the EP were found in the areas of the hydroxymethylene groups of the cage dimer and the single hydroxy group as well as the urea carbonyl group of A-98881, respectively. In order to compare the binding possibilities to the enzyme HIV-1 protease for the cage dimer and A-98881, their interaction fields with certain probes (CH3 for alkyl, NHamide, and carbonyl, O- of CO O-), representing the decisive functional groups of the active site, have b een calculated using GRID and projected into the enzyme placing the structu res according to the position of A-98881 in the enzyme-inhibitor complex. T he strongest calculated fields of the O- probe were found near Asp 25 for b oth structures. Another respective conformity consists in the overlap of th e fields for the NHamide probe near Ile 50 and 50' for the investigated cag e dimer and A-98881.