Sj. Titmuss et al., Docking experiments in the flexible non-nucleoside inhibitor binding pocket of HIV-1 reverse transcriptase, BIO MED CH, 7(6), 1999, pp. 1163-1170
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.