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 str uctures of HIV-I reverse transcriptase complexes with various non-nucleosid e 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. Doc king this database into each of the reverse transcriptase binding pockets s howed that all inhibitors could be fitted into each different pocket, witho ut alteration of the pocket geometry. This contradicts findings from earlie r docking investigations and implies that the conformation of the binding p ocket in each different complex is conserved sufficiently to allow particul ar uniform ligand binding modes. The inhibitor conformations selected by th is docking process are mostly the same as the one the ligand adopts in its own pocket and the selected conformations and orientations exhibit an impre ssive degree of similarity in the arrangement of their steric and electroni c features. A correlation has also been observed between inhibitor flexibil ity and tightness of fit into the pockets with the more flexible inhibitors achieving a tighter fit and thus fewer favourable orientations upon dockin g. (C) 1999 Elsevier Science Ltd. All rights reserved.