Vincent Théry

Quantum mechanical computations on very large molecular systems: the local self-consistent field method

Quantum chemical computations on a subset of a large molecule can be performed, at the neglect of diatomic differential overlap (NDDO) level, without further approximation provided that the atomic orbitals of the frontier atoms are replaced by parametrized orthogonal hybrid orbitals. The electrostatic interaction with the rest of the molecule, treated classically by the usual molecular mechanical approximations, is included into the self‐consistent field (SCF) equations. The first and second derivatives of energy are obtained analytically, allowing the search for energy minima and transition states as well as the resolution of Newton equations in molecular dynamics simulations. The local self‐consistent field (LSCF) method based on these approximations is tested by studying the intramolecular proton transfer in a Gly‐Arg‐Glu‐Gly model tetrapeptide, which reveals an excellent agreement between a computation performed on the whole molecule and the results obtained by the present method, especially if the quantum subsystem includes the side chains and the peptidic unit in between. The merits of the LSCF method are examplified by a study of proton transfer in the Asp69—Arg71 salt bridge in dihydrofolate reductase. Simulations of large systems, involving local changes of electronic structure, are therefore possible at a good degree of approximation by introducing a quantum chemical part in molecular dynamics studies. This methodology is expected to be very useful for reactivity studies in biomolecules or at the surface of covalent solids.

HYBRID CLASSICAL QUANTUM FORCE FIELD FOR MODELING VERY LARGE MOLECULES

A coherent computational scheme on a very large molecule in which the subsystem that undergoes the most important electronic changes is treated by a semiempirical quantum chemical method, though the rest of the molecule is described by a classical force field, has been proposed recently. The continuity between the two subsystems is obtained by a strictly localized bond orbital, which is assumed to have transferable properties determined on model molecules. The computation of the forces acting on the atoms is now operating, giving rise to a hybrid classical quantum force field (CQFF) which allows full energy minimization and modeling chemical changes in large biomolecules. As an illustrative example, we study the short hydrogen bonds and the proton-exchange process in the histidine-aspartic acid system of the catalytic triad of human neutrophil elastase. The CQFF approach reproduces the crystallographic data quite well, in opposition to a classical force field. The method also offers the possibility of switching off the electrostatic interaction between the quantum and the classical subsystems, allowing us to analyze the various components of the perturbation exerted by the macromolecule in the reactive part. Molecular dynamics confirm a fast proton exchange between the three possible energy wells. The method appears to be quite powerful and applicable to other cases of chemical interest such as surface reactivity of nonmetallic solids.

12-Helix folding of cyclobutane beta-amino acid oligomers.

The hexamer and octamer of trans-2-aminocyclobutane carboxylic acid were prepared and their conformational preferences studied experimentally and using molecular modeling. All observations suggest a marked preference for the folding of these oligomers into a well-defined 12-helical conformation, in both solution and the solid state.

Synthesis, Protein Kinase Inhibitory Potencies, and in Vitro Antiproliferative Activities of Meridianin Derivatives

The synthesis of new meridianin derivatives is described. The indolic ring system was substituted at the C-4 to C-7 positions either by a bromine atom or by nitro or amino groups. Additionally, an iodine atom or various aryl groups were introduced at the C-5 position of the 2-aminopyrimidine ring. These compounds as well as some of their synthetic intermediates were tested for their kinase inhibitory potencies and for their in vitro antiproliferative activities. We found that this series of compounds is particularly interesting in the development of new inhibitors of DYRK1A and CLK1 kinases. The most effective compounds toward these two kinase families are the 6- and 7-bromo derivatives 30, 33, and 34 that showed more than 45-fold selectivity toward DYRK1A/CLK1 kinases over the other kinases tested. Meridianin derivatives could thus be developed toward potent and selective inhibitors of key RNA splicing regulators and potential therapeutic agents.

Fructose‐1,6‐Bisphosphate Aldolase‐Mediated Synthesis of Aminocyclitols (Analogues of Valiolamine) and their Evaluation as Glycosidase Inhibitors

A highly stereoselective method for the preparation of nitro‐ and aminocyclitols, using fructose‐1,6‐bisphosphate aldolase, which catalyzes the aldol reaction of dihydroxyacetone phosphate (DHAP) on hydroxynitrobutanals, is reported. The key part of the synthesis is based on a one‐pot /two‐enzyme process whereby three reactions take place; rabbit muscle aldolase (RAMA) catalyzed aldolization, phytase‐catalyzed phosphate hydrolysis, and intramolecular spontaneous nitroaldolization. Two families of nitrocyclitols were obtained depending on the carbon configuration in the β position to the nitro group. Reduction of the latter afforded the aminocyclitols. Evaluation of the inhibition properties of the amines towards five commercially available glycosidases has shown selectivity for β‐glucosidase and β‐galactosidase.

Synthesis, Pim kinase inhibitory potencies and in vitro antiproliferative activities of diversely substituted pyrrolo[2,3-a]carbazoles.

The synthesis of new pyrrolo[2,3-a]carbazole derivatives diversely substituted at the C-6 to C-9 positions is described. These compounds were tested for their kinase inhibitory potencies toward three kinases (Pim-1, Pim-2, Pim-3) as well as for their in vitro antiproliferative activities toward a human fibroblast primary culture and three human solid cancer cell lines (PC3, DU145, and PA 1). Moreover, molecular docking studies were performed to explain the enhanced inhibitory activity of the most active compound 3d.

Identification of 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles as new Pim kinase inhibitors

New 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles were prepared and evaluated for their Pim kinase inhibitory potencies as well as their antiproliferative activities toward two prostatic cancer cell lines. Pyrazolocarbazole 15a was found to be a potent Pim kinase modulator with inhibitory potency toward the three isoforms. Compound 6c strongly inhibited Pim-3 with weaker effect toward Pim-1 and Pim-2, and thus could be used as an interesting molecular tool to study Pim-3 biological functions.

Identification of pyrrolo[2,3-g]indazoles as new Pim kinase inhibitors.

The synthesis and Pim kinase inhibition potency of a new series of pyrrolo[2,3-g]indazole derivatives is described. The results obtained in this preliminary structure-activity relationship study pointed out that sub-micromolar Pim-1 and Pim-3 inhibitory potencies could be obtained in this series, more particularly for compounds 10 and 20, showing that pyrrolo[2,3-g]indazole scaffold could be used for the development of new potent Pim kinase inhibitors. Molecular modeling experiments were also performed to study the binding mode of these compounds in Pim-3 ATP-binding pocket.

Synthesis and biological activities of 4-substituted pyrrolo[2,3-a]carbazole Pim kinase inhibitors.

Pyrrolo[2,3-a]carbazole-3-carbaldehydes are potent Pim kinase inhibitors with in vitro antiproliferative activities. In the present study, we report the synthesis and biological activities (Pim kinase inhibition and in vitro antiproliferative potency) of new 4-substituted pyrrolo[2,3-a]carbazoles. The results demonstrated that the Pim kinase inhibitory potency (especially Pim-3) can be conserved for pyrrolo[2,3-a]carbazoles bearing a methoxycarbonyl group at the 4-position without a formyl at the 3-position. Moreover, compound 27 that was found to be active against Pim-1 and Pim-3 kinases showed antiproliferative activities in the micromolar range.

Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co–crystal structure

The design and synthesis of new pyrido[3,4-g]quinazoline derivatives is described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A). The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/DYRK1A activity was validated by nanomolar potencies (compounds 12 and 13). CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket.