Computational Study of KNI-272, a Potent Inhibitor of HIV-1 Protease: On the Mechanism of Preorganization

David, Laurent; Luo, Ray; Head, Martha S.; Gilson, Michael K.

doi:10.1021/jp983675l

Cited by 22 publications

(19 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our applications of a GB model 3 in which atomic selfenergies are estimated with a charge-induced dipole term, 36 have yielded good agreement with experiment for pK a shifts in small molecules, 37 ion-pairing in aqueous solution, 38 the binding affinities of small molecules in chloroform, 39 conformational analysis of a potent HIV protease inhibitor, 40 and the association of adenine with synthetic adenine receptors (article in preparation). On the other hand, the GB model was not particularly effective at selecting the correct bound conformation of protein-ligand complexes, 41 and it gave somewhat unsatisfying results in calculations of the pK a s of ionizable groups in a protein active site.…”

mentioning

confidence: 73%

See 1 more Smart Citation

Comparison of generalized born and poisson models: Energetics and dynamics of HIV protease

2000

Self Cite

View full text Add to dashboard Cite

mentioning

confidence: 73%

“…All three simulations use the same initial structure of HIV-1 protease with an empty active site. The initial conformation was drawn from the crystal structure of HIV-1 PR with the inhibitor KNI-272, 40 but the inhibitor was deleted. Polar hydrogen coordinates were reconstructed with the program QUANTA.…”

Section: Dynamics Comparisonsmentioning

confidence: 99%

Comparison of generalized born and poisson models: Energetics and dynamics of HIV protease

2000

Self Cite

View full text Add to dashboard Cite

“…It is not clear that these large numbers are supported by experimental or theoretical evidence. Indeed, NMR studies frequently reveal marked conformational preferences of drug-like compounds in solution, such as the ''folded'' conformation of tandospirone (18) and the preorganized conformation of KNI-272, despite its 15 rotatable bonds (19). Such results weigh against the suitability of ligand rotamer counting as a basis for estimating the loss of ligand entropy on binding.…”

Section: Discussionmentioning

confidence: 99%

Ligand configurational entropy and protein binding

Chang

Chen

Gilson

2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

384

424

View full text Add to dashboard Cite

The restriction of a small molecule's motion on binding to a protein causes a loss of configurational entropy, and thus a penalty in binding affinity. Some energy models used in computer-aided ligand design neglect this entropic penalty, whereas others account for it based on an expected drop in the number of accessible rotamers upon binding. However, the validity of the physical assumptions underlying the various approaches is largely unexamined. The present study addresses this issue by using Mining Minima calculations to analyze the association of amprenavir with HIV protease. The computed loss in ligand configurational entropy is large, contributing ϳ25 kcal/mol (4.184 kJ/kcal) to ⌬G°. Most of this loss results from narrower energy wells in the bound state, rather than a drop in the number of accessible rotamers. Coupling among rotation/translation and internal degrees of freedom complicates the decomposition of the entropy change into additive terms. The results highlight the potential to gain affinity by designing conformationally restricted ligands and have implications for the formulation of energy models for ligand scoring.drug design ͉ translation ͉ rotamer ͉ affinity ͉ rotation A drug-like molecule that binds a protein becomes less mobile, and the resulting loss in configurational entropy opposes the attractive forces that drive binding. A number of empirical energy models used in virtual ligand screening include a term to account for this entropic penalty, but the underlying physics is not well characterized and hence merits critical examination. For example, most energy models assume that the ligand's entropy change can be decomposed into additive components, although correlated motions could lead to nonadditivity (see, e.g., refs. 1 and 2). Also, energy models often account for changes in torsional entropy with a term related to the number of rotatable bonds in the ligand, based on reasoning about the number of rotamers each bond can adopt (e.g., refs. 3-8) and a computational analysis of changes in vibrational and conformational entropy on protein folding (9). However, the physical rationale and accuracy of this approach is largely unexamined, especially in the context of protein-ligand binding. Similarly, the common assumption that changes in rotational and translational entropy are constant from one ligand to another appears to be unsupported.Recent calculations with the second-generation Mining Minima algorithm (M2) have provided insight into changes in configurational entropy upon binding for small host-guest systems (10, 11). The computed entropic penalty was found to range as high as ϳ20 kcal/mol, considerably more than typically assumed in ligandprotein scoring functions. The validity of these results is supported by the fact that the computed binding free energies were accurate to within ϳ1 kcal/mol. The entropy change was furthermore found to vary significantly across complexes of the same ligand with different receptors and even across different bound conformations of the same ligand and...

show abstract

“…15,16 The MM method yields a list of the most stable conformationssenergy wellssfor a molecule or complex. Each conformation i is associated with a free energy G′ i .…”

Section: Methodsmentioning

confidence: 99%

Differential Adsorption of Phenol Derivatives onto a Polymeric Sorbent: A Combined Molecular Modeling and Experimental Study

et al. 1999

View full text Add to dashboard Cite

Oxygenated aromatic compounds (OACs) are used for the synthesis of a variety of commercial products. Lignin from wood and other plant products are potential sources of OACs, but it is difficult to separate the mixtures of OACs found in digests of these raw materials. One promising separation approach involves the use of selective adsorption resins, such as the acrylic ester sorbent XAD-7. It has been shown previously that this sorbent binds the para isomer of one OAC, methoxyphenol, more favorably that the ortho isomer when hexane is used as the solvent. The present study uses a combination of molecular modeling and experiment to elucidate the mechanism of this selectivity. The calculations yield good agreement with experimental binding affinities and indicate that hydrogen bonding is the dominant mode of adsorption of para-methoxyphenol onto XAD-7 from hexane. In contrast, ortho-methoxyphenol appears to form an intramolecular hydrogen bond that weakens the intermolecular hydrogen bond to the sorbent. As a consequence, ortho-methoxyphenol binds less strongly, and its association is dominated by van der Waals interactions and three-centered hydrogen bonds. This result is supported by quantum mechanical calculations and infrared spectroscopic experiments. It is also found that when water is the solvent, hydrogen bonding becomes an insignificant adsorption mechanism, and both molecules bind to the resin via nonpolar interactions. This explains the loss of selectivity that is observed in both experiment and calculation.

show abstract

Computational Study of KNI-272, a Potent Inhibitor of HIV-1 Protease: On the Mechanism of Preorganization

Cited by 22 publications

References 19 publications

Comparison of generalized born and poisson models: Energetics and dynamics of HIV protease

Comparison of generalized born and poisson models: Energetics and dynamics of HIV protease

Ligand configurational entropy and protein binding

Differential Adsorption of Phenol Derivatives onto a Polymeric Sorbent: A Combined Molecular Modeling and Experimental Study

Contact Info

Product

Resources

About