2009
DOI: 10.1021/jm8009525
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Additivity in the Analysis and Design of HIV Protease Inhibitors

Abstract: We explore the applicability of an additive treatment of substituent effects to the analysis and design of HIV protease inhibitors. Affinity data for a set of inhibitors with a common chemical framework were analyzed to provide estimates of the free energy contribution of each chemical substituent. These estimates were then used to design new inhibitors, whose high affinities were confirmed by synthesis and experimental testing. Derivations of additive models by least-squares and ridgeregression methods were f… Show more

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Cited by 23 publications
(22 citation statements)
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“…92 One may thus conclude that an additive model is much more likely to be successful when applied to relative binding free energies than total binding free energies. 124,125 …”
Section: Ligand Efficiency and Additivity Analysis Of Binding Freementioning
confidence: 99%
“…92 One may thus conclude that an additive model is much more likely to be successful when applied to relative binding free energies than total binding free energies. 124,125 …”
Section: Ligand Efficiency and Additivity Analysis Of Binding Freementioning
confidence: 99%
“…Strictly speaking, this is an approximation because the contributions are not additive, but its utility is demonstrated by the observation that it reproduces the experimental trend, consistent with previous studies. 39 …”
Section: Methodsmentioning
confidence: 99%
“…The binding sites were recognized through a geometric-electrostatic docking full scan by MolFit [34]. Flexible ligand docking was then carried out using AutoDock and the binding complexes were imported to the Discover3 module in Insight II [35] for final refinement. Binding free energies were calculated by the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method implemented in Amber9.…”
Section: Entry Inhibitorsmentioning
confidence: 99%