Theoretical calculations of a model of NOS indazole inhibitors: Interaction of aromatic compounds with Zn-porphyrins José Elguero a, * , Ibon Alkorta a , Rosa M. Claramunt b , Concepción López b , Dionísia Sanz b , Dolores Santa María b a Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain b Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain article info Article history: Received 30 July 2009 Revised 28 September 2009 Accepted 5 October 2009 Available online 9 October 2009 Keywords: NOS Indazole Porphyrin DFT Stacking abstract We report a theoretical approach, at the M05-2x/6-311+G(d) level, to explain the affinity of indazoles for nitric oxide synthases using a simplified model of porphyrin. The theoretical E rel = E i stacking–E i apical values correlate with the experimental inhibition percents allowing to predict that 3,7-dinitro-1H-inda- zole should be a good NOS inhibitor. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction According to literature results concerning the structures of indazoles bound to any isoform of NOS (nitric oxide synthase: I or neuronal, II or inducible and III or endothelial), nitroindazoles position themselves above the heme 1 adopting two stacking modes called O–N and N–N. 1,2 These modes differ only on the HBs of the nitroindazole forms with other residues of the protein. In addition, Porubsky, Meneely and Scott reported the structure of indazole coordinated through its lone pair (LP model) to the heme iron (Scheme 1) of cytochrome P-450 2E1 in a similar way to 4-methylpyrazole as well as histidine residues. 3 Theoretical studies of stacking between different types of aro- matic molecules have received considerable attention. These stud- ies include benzene, 4 porphyrins, 5 and many other structures. 6,7 Ligand coordination is a classical problem that has been theoreti- cally approached in the case of zinc porphyrins complexes to sp 3 amines. 8 Computationally, Truhlar functionals like M05-2x, are particularly well adapted to stacking calculations. 9 We have re- placed the iron of the heme by zinc also present in many important porphyrins 10,11 to simplify the calculations and besides we re- moved all the C-substituents in 1. Ellison and Scheidt reported the X-ray structures of Fe-octaethylporphyrins bearing on the metal both an NO ligand and an heterocycle: the distances iron- N(heterocycle) are 1.99 Å (1-methylimidazole), 1.99 Å (pyrazole) and 2.01 Å (indazole). 12 2. Computational details The geometry of the systems was initially optimized at the M05-2x/6-311+G(d) computational level. 9,13 This functional has shown to provide a good description for a large variety of molecu- lar interaction complexes. 14 Frequency calculations at this compu- tational level were performed to confirm that the structures obtained correspond to energetic minima. All these calculations were carried out within the Gaussian 03 package. 15 3. Results and discussion We selected the series of aromatic compounds reported in Scheme 1. In the last years, we made several contributions to the analogies and differences of the benzene (3)/hexafluorobenzene (4) pair (aromaticity, stacking, complexes with ions); 16–19 thus, we start by comparing the complexes 2Á3 and 2Á4. Recently, it has been reported that naphthalene-porphyrin and azulene-porphyrin conjugates behave very differently. 20 Therefore, we decided to study the 2Á6 and 2Á7 complexes. 1,3,5-Trinitrobenzene (5) was selected to under- stand the behavior of nitroindazoles. We move then to aromatic heterocycles able to bind either by stacking or by their lone pairs: pyridine (8), 1H-imidazole (9), 0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2009.10.006 * Corresponding author. Tel.: +34 91 4110874; fax: +34 91 5644853. E-mail address: iqmbe17@iqm.csic.es (J. Elguero). Bioorganic & Medicinal Chemistry 17 (2009) 8027–8031 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc