Design and structure of symmetry-based inhibitors of HIV-1 protease


The concept of active-site symmetry along with structural and mechanistic considerations of aspartic proteases has been used to design novel,C 2-symmetry-based inhibitors of HIV PR. A comparative molecular-modeling strategy was used in the design of a pseudo-C 2-symmetric diaminoalcohol series and later a diastereomeric series ofC 2-symmetric diaminodiols. The structure of the pseudosymmetric alcohol A-74704, complexed with HIV PR, confirmed the proposed symmetric mode of binding, and also proved useful in subsequent efforts to improve the solubility of the more potent diol series. The crystal-structure analysis of a pseudosymmetricR,S-diol provided insights into the relative contributions of the two hydroxyl groups to the stability of the complex. A comparison of the binding modes for symmetric and asymmetric, substrate-based inhibitors indicates that the influence of symmetry on binding is mainly expressed at the protein level, since the overall subsite symmetry is maintained even with highly asymmetric inhibitors. Thus, while the incorporation ofC 2 symmetry does not necessarily lead to compounds with improved potency over asymmetric compounds, this strategy has led to the design of structurally novel and perhaps pharmacologically desirable inhibitors. The growing number of examples of symmetry-based inhibitors is evidence that symmetry has become a useful paradigm for HIV protease inhibitor design and that structure-based approaches to inhibitor design can contribute in unique and critical ways to the conceptualization of medicinal chemistry strategies that can lead to useful clinical candidates for AIDS, cancer and other diseases.

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Erickson, J.W. Design and structure of symmetry-based inhibitors of HIV-1 protease. Perspectives in Drug Discovery and Design 1, 109–128 (1993).

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Key words

  • AIDS
  • HIV protease
  • Drug design
  • Symmetric inhibitors
  • X-ray crystallography