Biomedical subjects

N Majeux

Publications and source records attributed to N Majeux.

6 recordsLinked to original sources

PubMed2001

Efficient electrostatic solvation model for protein-fragment docking.

A method is presented for the fast evaluation of the binding energy of a protein-small molecule complex with electrostatic solvation. It makes use of a fast preprocessing step based on the assumption that the main contribution to electrostatic desolvation upon ligand binding originates from the displacement of the first shell of water molecules. For a rigid protein, the precomputation of the energy contributions on a set of grids allows the estimation of the energy in solution of about 300 protein-fragment binding modes per second on a personal computer. The docking procedure is applied to five rigid binding sites whose size ranges from 17 residues to a whole protein of 107 amino acids. Using a library of 70 mainly rigid molecules, known micromolar inhibitors or close analogs are docked and prioritized correctly. The docking based rank-ordering of the library requires about 5 h and is proposed as a complementary approach to structure-activity relationships by nuclear magnetic resonance. Proteins 2001;42:256-268.

Binding Sites↗

PubMed2001

Hydrophobicity and functionality maps of farnesyltransferase.

Farnesyltransferase (FTase) catalyzes the attachment of a 15-carbon isoprenoid moiety, farnesyl, through a thioether linkage to a cysteine near the C-terminus of oncogenic Ras proteins. These transform animal cells to a malignant phenotype when farnesylated. Hence, FTase is an interesting target for the development of antitumor agents. In this work we first investigate the active site of FTase by mapping its hydrophobic patches. Then the program SEED is used to dock functional groups into the active site by an exhaustive search and efficient evaluation of the binding energy with solvation. The electrostatic energy is SEED is based on the continuum dielectric approximation and consists of screened intermolecular energy and protein and fragment desolvation terms. The results are found to be consistent with the sequence variability of the tetrapeptide substrate. The distribution of functional groups (functionality maps) on the substrate binding site allows for identification of modifications of the tetrapeptide sequence that are consistent with potent peptidic inhibitors. Furthermore, the best minima of benzene match corresponding moieties of an inhibitor in clinical trials. The functionality maps are also used to design a library of disubstituted indoles that might prevent the binding of the protein substrates.

Alkyl and Aryl Transferases↗

PubMed2001

Fragment-Based flexible ligand docking by evolutionary optimization.

A new computational approach for the efficient docking of flexible ligands in a rigid protein is presented. It exploits the binding modes of functional groups determined by an exhaustive search with solvation. The search in ligand conformational space is performed by a genetic algorithm whose scoring function approximates steric effects and intermolecular hydrogen bonds. Ligand conformations generated by the genetic algorithm are docked in the protein binding site by optimizing the fit of their fragments to optimal positions of chemically related functional groups. We show that the use of optimal binding modes of molecular fragments allows to dock known inhibitors with about ten rotatable bonds in the active site of the uncomplexed and complexed conformations of thrombin and HIV-1 protease.

Algorithms↗

PubMed2001

An evolutionary approach for structure-based design of natural and non-natural peptidic ligands.

A new computational approach (PEP) is presented for the structure-based design of linear polymeric ligands consisting of any type of amino acid. Ligands are grown from a seed by iteratively adding amino acids to the growing construct. The search in chemical space is performed by a build-up approach which employs all of the residues of a user-defined library. At every growing step, a genetic algorithm is used for conformational optimization of the last added monomer inside the binding site of a rigid target protein. The binding energy with electrostatic solvation is evaluated to select sequences for further growing. PEP is tested on the peptide substrate binding site of the insulin receptor tyrosine kinase and farnesyltransferase. In both test cases, the peptides designed by PEP correspond to the sequence motifs of known substrates. For tyrosine kinase, tyrosine residues are suggested at position P and P+2. While the tyrosine at P is in agreement with the experimental data, the one at P+2 is a prediction which awaits experimental validation. For farnesyltransferase, it is shown that electrostatic solvation is necessary for the correct design of peptidic inhibitors.

Algorithms↗

PubMed1999

Hydrophobicity at the surface of proteins.

A new method is presented to quantitatively estimate and graphically display the propensity of nonpolar groups to bind at the surface of proteins. It is based on the calculation of the binding energy, i.e., van der Waals interaction plus protein electrostatic desolvation, of a nonpolar probe sphere rolled over the protein surface, and on the color coding of this quantity on a smooth molecular surface (hydrophobicity map). The method is validated on ten protein-ligand complexes and is shown to distinguish precisely where polar and nonpolar groups preferentially bind. Comparisons with existing approaches, like the display of the electrostatic potential or the curvature, illustrate the advantages and the better predictive power of the present method. Hydrophobicity maps will play an important role in the characterization of binding sites for the large number of proteins emerging from the genome projects and structure modeling approaches.

Alkyl and Aryl Transferases↗

PubMed1999

Exhaustive docking of molecular fragments with electrostatic solvation.

A new method is presented for docking molecular fragments to a rigid protein with evaluation of the binding energy. Polar fragments are docked with at least one hydrogen bond with the protein while apolar fragments are positioned in the hydrophobic pockets. The electrostatic contribution to the binding energy, which consists of screened intermolecular energy and protein and fragment desolvation terms, is evaluated efficiently by a numerical approach based on the continuum dielectric approximation. The latter is also used to predetermine the hydrophobic pockets of the protein by rolling a low dielectric sphere over the protein surface and calculating the electrostatic desolvation of the protein and van der Waals interaction energy. The method was implemented in the program SEED (solvation energy for exhaustive docking). The SEED continuum electrostatic approach has been successfully validated by a comparison with finite difference solutions of the Poisson equation for more than 2,500 complexes of small molecules with thrombin and the monomer of HIV-1 aspartic proteinase. The fragments docked by SEED in the active site of thrombin reproduce the structural features of the interaction patterns between known inhibitors and thrombin. Moreover, the combinatorial connection of these fragments yields a number of compounds that are very similar to potent inhibitors of thrombin. Proteins 1999;37:88-105.

Computer Simulation↗