Comparative ligand-based

Given the relative simplicity of ligand-based methods, it is interesting to note that in only comparatively few published reports of VS successes do the authors rely primarily on ligand-based methods. Of these studies, most appear to combine an interest in a given target with an interest in providing proof-of-concept for some extension of chemoinformatic theory. 

Pendent arm 1,4,7-triazacyclononane macrocycles (91) and (92) have been used to stabilize the zinc-to-phenoxyl bond allowing characterization of these compounds.477 The interest in the zinc complexes comes from the wide potential range in which it is redox stable allowing observation of the ligand-based redox processes, this allows study of the radical by EPR and the electronic spectra is unperturbed by d-d transitions. Macrocycles of the type l,4,7-tris(2-hydroxybenzyl)-1,4,7-triazacylononane form a bound phenoxyl radical in a reversible one-electron oxidation of the ligand. The EPR, resonance Raman, electronic spectra, and crystal structure of the phenoxide complexes were reported. This compound can be compared to a zinc complex with a non-coordinated phenoxyl radical as a pendent from the ligand.735... 

Phosphoramidite ligands based on TADDOL (36) and on D-mannitol (37) [74] have also been used (Scheme 28.11). However, the enantioselectivities reported for the hydrogenation of a-dehydroamino acids and itaconates were generally lower compared to the ligands based on BINOL. A different strategy is the use of ligands 38a-g based on the achiral diol catechol, and chiral amines [75]. 

Evers, A., Hessler, G., Matter, H. and Klabunde, T. (2005) Virtual screening of biogenic amine-binding G-protein coupled receptors comparative evaluation of protein- and ligand-based virtual screening protocols. 

Another retrospective analysis of already known H DAC inhibitors was carried out by You et al. [68]. They generated a 3D chemical-feature-based pharmacophore model and compared the ligand-based model with the structural-functional requirements for the binding of the HDAC inhibitors. Using this model, the interactions between the benzamide MS-275 and HDAC were explored. The result showed that the type and spatial location of chemical features encoded in the pharmacophore are in full agreement with the enzyme-inhibitor interaction pattern identified from molecular docking. However, also in this study no experimental validation of the modeling results was provided. 

The oxidation of a Cr24+ paddlewheel complex had previously been studied by X-band EPR but revealed only a single line near g = 2. However, at 95 GHz the analysis40 of the spectra of Cr2[(PhN)2CN(CH2)4]4PF6 and [Mo2(TiPB)4]PF6, where (TiPB) is the anion of 2,4,6-triisopropylbenzoic acid, provided the values for Cr of = 1.9701 and gt — 1.9767, and for Mo of = 1.9427, gyy = 1.9358 and g%% — 1.9310. The unpaired electrons were deduced to reside on the metal-based, rather than the ligand-based, orbitals. This proved that for both Cr and Mo the complex is of the form M25+ and correct the attribution for Cr based on the X-band spectra. This was the first confirmed report of the oxidation of a Cr24+ paddlewheel complex comparable to the Mo25+ compounds. 

---