Electrostatic potential as an experimental or a theoretical tool for a better understanding of drug interactions

High-resolution X-ray diffraction and theoretical calculations allow a fine characterization of these electronic and electrostatic properties in crystals, which is essential to the understanding and prediction of the interaction of drugs with the biological targets (pharmacology) and excipients (formulation). This fundamental approach can have important consequences for practical applications in the areas of drug design or drug delivery. The Laboratoire Structures, Propriétés et Modélisation des Solides, SPMS (UMR 8580, CNRS / Ecole Centrale Paris), who will lead the proposed project, has developed a dual experimental and theoretical expertise in this field. Since 2002, we have expanded our approach combining high-resolution X-ray diffraction and ab initio calculations to the characterization of pharmaceutical solids through a joint research group (“Pharmaceutical Materials”) involving SPMS and the Laboratoire de Physico-chimie, Pharmacotechnie, Biopharmacie, PPB (UMR 8612 – CNRS / Paris Sud) of the Faculté de Pharmacie of Châtenay-Malabry. Our collaborative work has enabled us to answer several questions posed by medicinal chemists or galenists, in particular relative to the following topics: - Electronic and electrostatic properties of racemic ibuprofen [1] - Electronic and electrostatic properties of a complex of zinc aspirin [2] - Understanding of the crystallization of busulfan, a pediatric cancer chemotherapeutic drug, and development of a new formulation (encapsulation in a cyclodextrine derivate) [3] - Understanding of the reactivity toward nucleophile agent: a putative intermediary product in the total synthesis of cephalotaxine (antileukemic agent) [4] - Electronic and electrostatic properties of co-crystal of decavanadate – cytosine, compound implied in the activity or inhibition of various enzymes (phosphotransferases, Ca2+ ATP-ase, adenylate kinase, and others) [5] - Experimental and theoretical electrostatic properties of salicyladehyde thiosemicarbazone, a pharmacophore of trombopoietin mimics, one of the simplest ligands in the thiosemicarbazone family [6] - Experimental and theoretical electrostatic properties of styrylquinoline-based compounds as new inhibitors in the integrase of the HIV-1 [7,8]. In this talk we will present results concerning the above-cited compounds. In the abstract, we will focuse on our work on the electrostatic properties of HIV-1 integrase inhibitors [7,8] in collaboration with the team of d'Angelo (Laboratoire BIOCIS, UMR 8076, CNRS - Paris-Sud). The most promising candidate from the point of view of its therapeutic indicators (in vitro inhibition, ex vivo and toxicity) is (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinoline carboxylic acid. This compound is in pre-clinical development phase (Bio-Alliance star-up). Crystals are very small and air sensitive. Single X-ray diffraction has permitted the determination of the molecular structure of the inhibitor, evidencing its zwiterionic character, but the quality of the crystals was not sufficient for high resolution even with experiments using ESRF synchrotron radiation. The two precursors have also being crystallized and the electron density has been determined. Experimental – theory (HF and DFT) comparisons have shown that there is no electronic delocalization between the two fragments when the spacer is ethylenic. Experiments have been conducted to synthesize several compounds similar to I changing the nature of the spacer and also the functional groups on the hydroxylated aromatic ring [9]. In complement, a systematic approach based on Kohonen neural network was also explored [10]. While conclusions on the role of these groups arose and then allowed for the synthesis of optimized molecules, the influence of the spacer on the activity of the inhibitors remained unclear. Among a hundred quinolines derivatives already synthesized we selected and compared molecules which exhibit various ability to inhibit the integrase. By means of first principals quantum chemistry computations, we aim at drawing from this comparison electrostatic criteria enable to predict which molecules are likely to be active. From our results we try to conclude to what extend their structure play a role in the reactional mechanism. Figure : Electrostatic theoretical potential on the molecular surface (right) and isosurfaces of one integrase inhibitor. Zwiterionic form (up) and non-zwiterionic form (down). [8] [1] BOUHMAIDA N., DUTHEIL M., GHERMANI N. E. and BECKER P. «Gradient vector field and properties of the experimental electrostatic potential: application to Ibuprofen drug molecule. », J. Chem. Phys., 2002, 116, 6196-6204 [2] SPASOJEVIC - DE BIRE A., BOUHMAIDA N., KREMENOVIC A., MORGANT G. and GHERMANI N. E. «Experimental Electron Density and Electrostatic Potential Analysis of Zinc(Aspirinate)2(H2O)2 Complex: a 3d10 Metal Bonding to a Drug-ligand. », J. Phys Chem. A, 2002, 106, 12170-12177 [3] GHERMANI N. E., SPASOJEVIC - DE BIRÉ A., BOUHMAIDA N., OUHARZOUNE S., BOULIGAND J., LAYRE A., GREF R. and COUVREUR P. « Molecular Reactivity of the Busulfan Through its Experimental Electrostatic Properties in the Solid State. », Pharmaceutical Research, 2004, 21, 598-607 [4] PIZZONERO M., KELLER L., DUMAS F., OUREVITCH M., MORGANT G., GHERMANI N. E., SPASOJEVIC - DE BIRE A., BOGDANOVIC G. and d'ANGELO J. «Crystallographic/Electron Density Characterizations and Reactions with Nucleophiles of Β-Enaminonitriles Possessing a Pyrrolobenzazepine Core. », J. Org. Chem., 2004, 69, 4336-4350 [5] BOSNJAKOVIC-PAVLOVIC N., CORREIA I., TOMAZ I., BOUHMAIDA N., AVECILLA F., SPASOJEVIC-DE BIRÉ A., MIOC U., PESSOA J., GHERMANI NE. « Structure et Propriétés Electrostatiques d'un Complexe Décavanadate-Cytosine. », Colloque de l'Association Française de Cristallographie, AFC 2003. Caen (F), july 2003 [6] NOVAKOVIC S., COURCOT B., FRAISSE B., LEOVAC V., BOGDANOVIC G.A., SPASOJEVIC-DE BIRÉ A., « Experimental and theoretical electrostatic properties of salicylaldehyde thiosemicarbazone. », 5th World Meeting on Pharmaceutics Biopharmaceutics and Pharmaceutical Technology, Geneva (CH), march 2006 [7] FIRLEY D., FRAISSE B., ZOUHIRI, F., SPASOJEVIC - DE BIRE A., DESMAËLE D., D'ANGELO J. and GHERMANI N. E. «7-Carboxylato-8-hydroxy-2-methylquinoliniummonohydrate and 7-carboxy-8-hydroxy-2-methylquinolinium chloridemonohydrate at 100 K », Acta Crystallogr., 2005, C61, o154-o157 [8] FIRLEY D., COURCOT B., GILLET J.M., FRAISSE B., ZOUHIRI F., DESMAELE D., D'ANGELO J., GHERMANI N. E., "Experimental/Theoretical Electrostatic Properties of a Styrylquinoline-Type HIV-1 Integrase Inhibitor and Its Progenitors", Journal of Physical Chemistry B, 2006, 110, 537-547. [9] BENARD, C., ZOUHIRI, F., NORMAND-BAYLE, M., DANET, M., DESMAËLE, D., LEH, H., MOUSCADET, J.F., MBEMBA, G., THOMAS, C.M., BONNENFANT, S., LE BRET, M. D'ANGELO, “Linker-modified quinoline derivatives targeting HIV-1 integrase: synthesis and biological activity”J. Bioorg. Med. Chem. Lett., 2004, 14, 2473-2476 [10] POLANSKI, J., ZOUHIRI, F., JEANSON, L., DESMAËLE, D., D'ANGELO, J., MOUSCADET, J.F., GIELECIAK,R., GASTEIGER, J. LE BRET, M. “Use of the Kohonen neural network for rapid screening of ex vivo anti-HIV activity of styrylquinolines” J.Med.Chem. 2002, 45, 4647-465