Biomedical subjects

Irwin D Kuntz

Publications and source records attributed to Irwin D Kuntz.

8 recordsLinked to original sources

PubMed2003

Molecular recognition and docking algorithms.

Molecular docking is an invaluable tool in modern drug discovery. This review focuses on methodological developments relevant to the field of molecular docking. The forces important in molecular recognition are reviewed and followed by a discussion of how different scoring functions account for these forces. More recent applications of computational chemistry tools involve library design and database screening. Last, we summarize several critical methodological issues that must be addressed in future developments.

Algorithms↗

PubMed2003

Free energy calculations for theophylline binding to an RNA aptamer: Comparison of MM-PBSA and thermodynamic integration methods.

We have applied the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method (J. Srinivasan, T. E. Cheatham, P. Cieplak, P. A. Kollman, and D. A. Case, Journal of the American Chemical Society, 1998, Vol. 120, pp. 9401-9409) to study the interaction of an RNA aptamer with theophylline and its analogs. The MM-PBSA free energy analysis provides a reasonable absolute binding free energy for the RNA aptamer-theophylline complex formation. Energetic analysis reveals that the van der Waals interaction and the nonpolar contribution to solvation provide the basis for the favorable absolute free energy of complex. This trend is similar to other protein-ligand interactions studied previously. The MM-PBSA method also ranks the relative binding energies of five theophylline analogs approximately correctly, but not as well as the more conventional thermodynamic integration calculations, which were carried out to convert theophylline into its analogs. The comparison of MM-PBSA with TI suggests that the MM-PBSA method has some difficulties with the first-solvation-shell energetics.

Binding Sites↗

PubMed2003

Direct hydroxide attack is a plausible mechanism for amidase antibody 43C9.

Direct hydroxide attack on the scissile carbonyl of the substrate has been suggested as a likely mechanism for esterase antibodies elicited by phosphonate haptens, which mimic the transition states for the alkaline hydrolysis of esters.1 The unique amidase activity of esterase antibody 43C9 has been attributed to nucleophilic attack by an active-site histidine residue.2 Yet, the active site of 43C9 is strikingly similar to those of other esterase antibodies, particularly 17E8. We have carried out quantum mechanical calculations, molecular dynamics simulations, and free energy calculations to assess the mechanism involving direct hydroxide attack for 43C9. Results support this mechanism and suggest that the mechanism is plausible for other antiphosphonate antibodies that catalyze the hydrolysis of (p-nitro)phenyl esters.

Amidohydrolases↗

PubMed2003

Information content of molecular structures.

For a completely enumerated set of conformers of a macromolecule or for exhaustive lattice walks of model polymers it is straightforward to use Shannon information theory to deduce the information content of the ensemble. It is also practicable to develop numerical measures of the information content of sets of exact distance constraints applied to specific conformational ensembles. We examine the effects of experimental uncertainties by considering "noisy" constraints. The introduction of noise requires additional assumptions about noise distribution and conformational clustering protocols that make the problem of measuring information content more complex. We make use of a standard concept in communication theory, the "noise sphere," to link uncertainty in measurements to information loss. Most of our numerical results are derived from two-dimensional lattice ensembles. Expressing results in terms of information per degree of freedom removes almost all of the chain length dependence. We also explore off-lattice polyalanine chains that yield surprisingly similar results.

Amino Acid Sequence↗

PubMed2002

Stability of macromolecular complexes.

Macromolecular interactions are crucial in numerous biologic processes, yet few general principles are available that establish firm expectations for the strength of these interactions or the expected contribution of specific forces. The simplest principle would be a monotonic increase in interactions as the size of the interface grows. The exact relationship might be linear or nonlinear depending on the nature of the forces involved. Simple "linear-free energy" relationships based on atomic properties have been well documented, for example, additivity for the interaction of small molecules with solvent, and, recently, have been explored for ligand-receptor interactions. Horton and Lewis propose such additivity based on buried surface area for protein-protein complexes. We investigated macromolecular interactions and found that the highest-affinity complexes do not fulfill this simple expectation. Instead, binding free energies of the tightest macromolecular complexes are roughly constant, independent of interface size, with the notable exception of DNA duplexes. By comparing these results to an earlier study of protein-ligand interactions we find that: (1) The maximum affinity is approximately 1.5 kcal/mol per nonhydrogen atom or 120 cal/mol A(2) of buried surface area, comparable to results of our earlier work; (2) the lack of an increase in affinity with interface size is likely due to nonthermodynamic factors, such as functional and evolutionary constraints rather than some fundamental physical limitation. The implication of these results have some importance for molecular design because they suggest that: (1) The stability of any given complex can be increased significantly if desired; (2) small molecule inhibitors of macromolecular interactions are feasible; and (3) different functional classes of protein-protein complexes exhibit differences in maximal stability, perhaps in response to differing evolutionary pressures. These results are consistent with the widespread observation that proteins have not evolved to maximize thermodynamic stability, but are only marginally stable.

Animals↗

PubMed2002

Molecular dynamics and free energy analyses of cathepsin D-inhibitor interactions: insight into structure-based ligand design.

In this study, we compare the calculated and experimental binding free energies for a combinatorial library of inhibitors of cathepsin D (CatD), an aspartyl protease. Using a molecular dynamics (MD)-based, continuum solvent method (MM-PBSA), we are able to reproduce the experimental binding affinity for a set of seven inhibitors with an average error of ca. 1 kcal/mol and a correlation coefficient of 0.98. By comparing the dynamical conformations of the inhibitors complexed with CatD with the initial conformations generated by CombiBuild (University of California, San Francisco, CA, 1995), we have found that the docking conformation observed in an X-ray structure of one peptide inhibitor bound to CatD (Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6796-6800) is in good agreement with our MD simulation. However, the DOCK scoring function, based on intermolecular van der Waals and electrostatics, using a distance-dependent dielectric constant (J. Comput. Chem. 1992, 13, 505-524), poorly reproduces the trend of experimental binding affinity for these inhibitors. Finally, the use of PROFEC (J. Comput.-Aided Mol. Des. 1998, 12, 215-227) analysis allowed us to identify two possible substitutions to improve the binding of one of the better inhibitors to CatD. This study offers hope that current methods of estimating the free energy of binding are accurate enough to be used in a multistep virtual screening protocol.

Algorithms↗

PubMed2002

A novel mechanism for inhibition of HIV-1 reverse transcriptase.

The human immunodeficiency virus (HIV) epidemic is an important medical problem. Although combination drug regimens have produced dramatic decreases in viral load, current therapies do not provide a cure for HIV infection. We have used structure-based design and combinatorial medicinal chemistry to identify potent and selective HIV-1 reverse transcriptase (RT) inhibitors that may work by a mechanism distinct from that of current HIV drugs. The most potent of these compounds (compound 4, 2-naphthalenesulfonic acid, 4-hydroxy-7-[[[[5-hydroxy-6-[(4-cinnamylphenyl)azo]-7-sulfo-2-naphthalenyl]amino]carbonyl]amino]-3-[(4-cinnamylphenyl)azo], disodium salt) has an IC(50) of 90 nM for inhibition of polymerase chain extension, a K(d) of 40 nM for inhibition of DNA-RT binding, and an IC(50) of 25-100 nM for inhibition of RNaseH cleavage. The parent compound (1) was as effective against 10 nucleoside and non-nucleoside resistant HIV-1 RT mutants as it was against the wild-type enzyme. Compound 4 inhibited HIV-1 RT and murine leukemia virus (MLV) RT, but it did not inhibit T(4) DNA polymerase, T(7) DNA polymerase, or the Klenow fragment at concentrations up to 200 nM. Finally, compound 4 protected cells from HIV-1 infection at a concentration more than 40 times lower than the concentration at which it caused cellular toxicity.

Algorithms↗

PubMed2002

Small molecule affinity fingerprinting. A tool for enzyme family subclassification, target identification, and inhibitor design.

Classifying proteins into functionally distinct families based only on primary sequence information remains a difficult task. We describe here a method to generate a large data set of small molecule affinity fingerprints for a group of closely related enzymes, the papain family of cysteine proteases. Binding data was generated for a library of inhibitors based on the ability of each compound to block active-site labeling of the target proteases by a covalent activity based probe (ABP). Clustering algorithms were used to automatically classify a reference group of proteases into subfamilies based on their small molecule affinity fingerprints. This approach was also used to identify cysteine protease targets modified by the ABP in complex proteomes by direct comparison of target affinity fingerprints with those of the reference library of proteases. Finally, experimental data were used to guide the development of a computational method that predicts small molecule inhibitors based on reported crystal structures. This method could ultimately be used with large enzyme families to aid in the design of selective inhibitors of targets based on limited structural/function information.

Algorithms↗