Experimental/theoretical electrostatic properties of a styrylquinoline-type HIV-1 integrase inhibitor and its progenitors.
We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.
Firley
Delphine
D
Laboratoire Structures, Propriétés et Modélisation des Solides, UMR CNRS 8580, Ecole Centrale Paris, Grande Voie des Vignes, 92295 Châtenay-Malabry Cedex, France.
Courcot
Blandine
B
Gillet
Jean-Michel
JM
Fraisse
Bernard
B
Zouhiri
Fatima
F
Desmaële
Didier
D
d'Angelo
Jean
J
Ghermani
Nour Eddine
NE
D002247:Carbon Isotopes; D003460:Crystallization; D004789:Enzyme Activation / Q000187:drug effects; D019427:HIV Integrase / Q000737:chemistry* / Q000187:drug effects; D019429:Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011237:Predictive Value of Tests; D011789:Quantum Theory; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012680:Sensitivity and Specificity; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D002247:Carbon Isotopes; D019429:Integrase Inhibitors; D011804:Quinolines; C481600:styrylquinoline; D019427:HIV Integrase