THE STRUCTURE OF THREE INHIBITORS IN COMPLEX WITH HIV-1 PROTEASE REVEALS THE IMPORTANCE OF STRUCTURAL WATERS
Hans O.
Andersson, Johan Hultén, Seved Löwgren, Nick M.
Bonham, Wesley Schaal, Anders Karlén, Anders Hallberg and
Torsten Unge
1Dept. of Molecular Biology, Uppsala
University, Uppsala, Sweden.
2Dept. of Organic Pharmaceutical
Chemistry, Uppsala University, Uppsala, Sweden.
E-mail: (Hans Andersson) hoa@alpha2.bmc.uu.se
Keywords: HIV, protease,
x-ray, structure, drug design
Human immunodeficiency virus type 1 protease (HIV-1 PR) is essential for virus maturation and is thus a suitable target for drug design. HIV-1 PR is a homodimer with the active site at the interface between the monomers. The dimer is asymmetric in its interaction with inhibitors.
We have determined the structures of two sulfamide compounds, AHA 024 and AHA030, and one urea compound, AHA008, in complexes with HIV-1 PR. AHA008 is chemically symmetric, with a methoxy-group on the P1- and P1'-arms. AHA008 binds with the assigned P1/P1'-arms in the respective S1/S1'-pockets. AHA024 has a configuration similar to previously determined structure of AHA006, where the arms on one side has flipped and bind with the P1-arm in the S2-pocket and the P2-arm in the S1-pocket (1). AHA024 is chemically asymmetric with a methoxy-group on one of the P1/P1'-arms and an methylacetyl-group on the other. AHA030 is chemically symmetric with an oxine-group on the P1- and P1'-arms.
AHA024 was constructed as to form a hybrid between a urea compound and a sulfamid compound, in such a way that the methylacetyl-group would force the compound to stay in the unflipped urea conformation.Our results showed that the sulfamid conformation seems to be favourable.
In all inhibitor complexes that we have studied, we have found structural waters situated between the P1/P1'-arms and between the P2/P2'-arms. The positions and interactions of the waters to HIV-1 PR differ between the compound complexes. The development of the inhibitors in such a way that the structural waters are displaced by side chains of the inhibitors, might lead to higher specificity and better binding properties. In a first attempt in order to acheave this the cyclic sulfamide compound, AHA030, was synthesized.
Our results show that structural
waters are very important and sometimes difficult to replace. In
AHA030 the oxine-groups, supposed to replace the two waters,
hydrogen-binds to Asp29 on one side and on the other side it is
pointing out into the solvent. Thus they did not displace any
waters. Further modelling and synthetic experiments are needed
for complete investigation of the importancy of the structural
waters.