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A preference‐based free‐energy parameterization of enzyme‐inhibitor binding. Applications to HIV‐1‐protease inhibitor design
Author(s) -
Wallqvist A.,
Jernigan R.L.,
Covell D.G.
Publication year - 1995
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1002/pro.5560040923
Subject(s) - protease inhibitor (pharmacology) , hiv 1 protease , enzyme , human immunodeficiency virus (hiv) , preference , enzyme inhibitor , protease , chemistry , biochemistry , virology , biology , mathematics , viral load , antiretroviral therapy , statistics
Abstract The interface between protein receptor‐ligand complexes has been studied with respect to their binary interatomic interactions. Crystal structure data have been used to catalogue surfaces buried by atoms from each member of a bound complex and determine a statistical preference for pairs of amino‐acid atoms. A simple free energy model of the receptor‐ligand system is constructed from these atom‐atom preferences and used to assess the energetic importance of interfacial interactions. The free energy approximation of binding strength in this model has a reliability of about ±1.5 kcal/mol, despite limited knowledge of the unbound states. The main utility of such a scheme lies in the identification of important stabilizing atomic interactions across the receptor‐ligand interface. Thus, apart from an overall hydrophobic attraction (Young L, Jernigan RL, Covell DG, 1994, Protein Sci 3 :717–729), a rich variety of specific interactions is observed. An analysis of 10 HIV‐1 protease inhibitor complexes is presented that reveals a common binding motif comprised of energetically important contacts with a rather limited set of atoms. Design improvements to existing HIV‐1 protease inhibitors are explored based on a detailed analysis of this binding motif.