CRYSTAL STRUCTURES OF HIV-1 RT AND NON-NUCLEOSIDE INHIBITOR COMPLEXES: IMPLICATIONS FOR DRUG DESIGN. Jingshan Ren¹, Robert Esnouf¹, Andrew Hopkins¹, Carl Ross², E.Yvonne Jones¹, Dave Stammers² and D.Stuart¹., ¹Laboratory of Molecular Biophysics, Rex Richards Building, South Parks Road, Oxford, OX1 3QU, UK., ²The Glaxo-Wellcome Research Laboratories, Langley Court, Beckenham, Kent, BR3 3BS, UK.

Crystal structures of a number of complexes of HIV-1 RT with non-nucleoside inhibitors (NNIs), including nevirapine, (-APA, 1051U91, HEPT, 9-Cl-TIBO, MKC-442 and TNK-651, have been determined at high resolution (Ren et al. 1995 Nature Struct. Biol. 2, 293-302; Esnouf et al. 1995 Nature Struct. Biol. 2, 303-308; Ren et al. 1995 Structure 3, 915-926; Hopkins et al. J. Med. Chem. in the press). All the inhibitors we have studied bind at same pocket formed between two (-sheets of the p66 palm, some 10 Šfrom the polymerase active site. The internal surface of the pocket is predominantly hydrophobic being constructed mainly from leucine, valine, tryptophan and tyrosine residues. The structures reveal a common mode of binding for these chemically diverse compounds. Each compound has its own particular structural characteristics and there is sufficient plasticity in certain regions of the surrounding protein to allow some unfavourable contacts to be relieved without changing the overall binding mode. The volume of the pocket varies with the inhibitors, ranging between some 600 and 700 ų, of which the inhibitors occupy in the order of 250-350 ų. However, much of the pocket lining remains very similar in all cases so that there is a very marked matching of shape in those compounds that occupy this volume. In some cases this is achieved by conformational rearrangement of the compound from its lowest energy structure in solution. These results allow us to understand the structural basis of the potency of the inhibitors and suggest possible modifications which should improve interactions with the enzyme.