Docking experiments in the flexible non-nucleoside inhibitor binding pocket of HIV-1 reverse transcriptase.

Docking experiments were undertaken using a number of published crystal structures of HIV-1 reverse transcriptase complexes with various non-nucleoside inhibitors. The docking method was validated by successfully docking each ligand, in the conformation found in the crystal structure of the complex with the enzyme, back into its binding pocket in the right orientation and position. Each ligand was then subjected to conformational searching and a database of unique low-energy conformations of all ligands established. Docking this database into each of the reverse transcriptase binding pockets showed that all inhibitors could be fitted into each different pocket, without alteration of the pocket geometry. This contradicts findings from earlier docking investigations and implies that the conformation of the binding pocket in each different complex is conserved sufficiently to allow particular uniform ligand binding modes. The inhibitor conformations selected by this docking process are mostly the same as the one the ligand adopts in its own pocket and the selected conformations and orientations exhibit an impressive degree of similarity in the arrangement of their steric and electronic features. A correlation has also been observed between inhibitor flexibility and tightness of fit into the pockets with the more flexible inhibitors achieving a tighter fit and thus fewer favourable orientations upon docking.