Issue in Honor of Prof. Vincenzo Tortorella ARKIVOC 2004 (v) 231-250
As demonstrated by numerous studies,11-17 electrostatics generally disfavor the docking of ligand and receptor molecules because of the unfavorable change in the electrostatics of solvation is mostly, but not fully, compensated by the favorable electrostatics within the resulting
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ligand-receptor complex. Indeed, the total electrostatic energy contributions ( values) for all 14DM/azole derivative complex formations are unfavorable, the 2a-e/14DM, the 2k-l/14DM and the miconazole/14DM complex formations being less unfavorable than the 2f-j/14DM complex formations because of a less positive total electrostatic term in which the penalty paid by the electrostatics of solvation is better compensated by favorable electrostatic interactions within the complex. Thus, even though electrostatics destabilize azole derivative/14DM complex formation, it is the optimized balance of opposing electrostatic contributions that leads to tighter binding both in the case of the reference compound miconazole, and in the series of compounds 2a-e and 2k-l.
Molecular dynamics simulations have thus shown to be able to rank binding affinities of all inhibitors, and to provide insight into the interactions occurring in the active site and the origins of variations in the corresponding binding free energy. Accordingly, the computational strategy used in this paper can provide a blueprint for new inhibitors in structure-based drug design or in predicting binding affinity of a ligand prior to organic synthesis.
Experimental Section
General Procedures. Melting points were determined with a Büchi 510 capillary apparatus, and are uncorrected. Infrared spectra in nujol mulls were recorded on a Jasco FT 200 spectrophotometer. Proton nuclear magnetic resonance (1H-NMR) spectra were determined on a Varian Gemini 200 spectrometer; chemical shifts are reported as d (ppm) in DMSOd6 solution. Reaction courses and product mixtures were routinely monitored by thin-layer chromatography (TLC) on silica gel precoated F254 Merck plates. ESI-MS spectra were obtained on a PE-API 1 spectrometer by infusion of a solution of the sample in MeOH. Elemental analyses (C, H, N) were performed on a Carlo Erba analyzer and were within ± 0.3 of the theoretical value.
Synthesis 1-(5-Bromo-thiophen-2-yl)-2-(1H-imidazol-1-yl)-ethanone (1k)
To a solution of 1.5 g (5.3 mmol) of 2-bromo-1-(5-bromo-thiophen-2-yl)-ethanone in 30 ml of tetrahydrofuran, 1.1 g (15.9 mmol) of imidazole were added under stirring. The reaction mixture was stirred at room temperature for 12 h. Thereafter, the solvent was removed under reduced pressure. The solid residue was dissolved in dichloromethane and the solution was washed with cold water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give a residue which was recrystallized from ethanol to give 1.3 g (83 %) of 1k; m. p. 158-160°C. IR (nujol, cm-1): 1668. 1H-NMR (DMSO-d6/TMS): d 5.58 (s, 2H, CH2), 6.89 (s, 1H, imid.), 7.10 (s, 1H, imid.), 7.45 (d, 1H, thioph.; J=3.66 Hz), 7.58 (s, 1H, imid.), 7.92 (d, 1H, thioph. J=
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