HIV protease: Structure-based design

Summary

Close examination of the X-ray crystallographic structures of complexes of prototypical HIV protease inhibitors drawn from diverse structural classes and bound to either synthetic or recombinant HIV protease reveals a remarkable degree of conservation vis-à-vis the protein's homodimeric backbone geometry and key features of its inhibitor binding site. Subtle concerted movements of the amino acid side chains lining this cavity and making contact with inhibitors are evident in exquisite detail in the most highly resolved structures. They are responsible for the enzyme's selectivity. As noted in the preceding perspective on X-ray crystallographic studies, HIV protease is rapidly becoming one of the most well-studied proteins.

As a modeler one is encouraged to use the available structural data to predict the binding modes of other classes of HIV protease inhibitors for which X-ray data are unavailable and also as templates to guide the design of further novel inhibitors, which hopefully have some advantages over existing structures. The improvements sought typically involve structural simplification, metabolic stability, or most of all, increased in vivo potency and oral bioavailability. While the structural outcome may or may not bear resemblance to any one of the original reference inhibitor structures, we refer to this process as one ofstructure-based design to emphasize its dependence on critical analyses of the properties and behavior of these experimental datasets.

Computational methodologies are available to analyze and compare these datasets in some depth, and to display and manipulate them interactively, in various complementary visualization formats, as a preliminary to undertaking any structurally directed synthetic initiatives. Likewise, efficient molecular-mechanics software tools are on hand to explore the conformational changes around the active site, which are needed to build in or to dock models of new inhibitor structures; either prospectively, for evaluation as potential synthetic targets, or retrospectively, to help rationalize the SAR of a known series or lead in the context of a more realistic active site-bound model.

To date these design techniques and strategies have been applied mainly to the optimization of established peptidomimetic leads and to rationalize the binding modes of new peptidomimetic inhibitor classes. However, examples exist of applications to the binding modes of nonpeptidic inhibitors and of limited attempts at de novo structure-based design.

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Clare, M. HIV protease: Structure-based design. Perspectives in Drug Discovery and Design 1, 49–68 (1993). https://doi.org/10.1007/BF02171655

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Key words

  • Enzyme
  • Inhibitor
  • Design
  • HIV-1
  • Protease