Comparative molecular field analysis of non-steroidal aromatase inhibitors related to fadrozole

Abstract

A series of non-steroidal inhibitors of aromatase, structurally related to fadrozole (2), was investigated with the aim of developing a 3D QSAR model using the Comparative Molecular Field Analysis (CoMFA) technique. The alignment of the molecules was performed following two approaches (atom-by-atom and field fit), both starting from an initial hypothesis of superimposition of fadrozole to a steroidal inhibitor (3). From a number of CoMFA models built with different characteristics, one was recognized as the most statistically relevant; this one is discussed in detail. The features of the 3D QSAR model are consistent with those of other 3D and QSAR models of aromatase and its inhibitors.

Nonsteroidal aromatase inhibitors: Recent advances

“…The result was the binding model illustrated in Figure 8, that allowed to rationalize some aspects of the SAR of NSAIs, and to depict accessible and nonaccessible volumes to ligands. 112 The aim of describing the SAR of NSAIs by means of a more comprehensive model was pursued by us 75,76 using the CoMFA approach, and taking advantage of the above described binding mode developed by Furet et al 112 as the basis for the alignment of the molecules. We aligned 49 NSAIs in agreement with that hypothesis, and calculated a statistical model able to describe the variations of inhibitory potency as function of the steric and electronic characteristics of the compounds.…”

“…75,76 It is known that the CoMFA analysis provides a quantitative description in terms of steric and electronic properties of favorable and unfavorable zones in the inhibitor space, after the compounds have been aligned onto a template molecule on the basis of a pharmacophoric hypothesis. 77 Given that the clearest indication coming from the CoMFA models for NSAIs 75,76 was the existence of a wide favorable steric zone located around the phenyl ring of the reference compound fadrozole, the consequent decision was to design molecules able to fill that area.…”

“…75,76 It is known that the CoMFA analysis provides a quantitative description in terms of steric and electronic properties of favorable and unfavorable zones in the inhibitor space, after the compounds have been aligned onto a template molecule on the basis of a pharmacophoric hypothesis. 77 Given that the clearest indication coming from the CoMFA models for NSAIs 75,76 was the existence of a wide favorable steric zone located around the phenyl ring of the reference compound fadrozole, the consequent decision was to design molecules able to fill that area. The compounds were built by taking the chromone and the xanthone nuclei as molecular skeletons, and by inserting on them the functions supposed to be critical for binding to the aromatase active site, i.e., an azole ring linked to the (di)benzopyranone aromatic moiety by a methylene unit, and an H-bond accepting function located on the aromatic ring at a suitable distance from the azole nitrogen atom carrying the lone pair.…”

The linear relationship between Koopmans' and hydrogen bond energies for some simple carbonyl molecules

“…For thermolysin inhibitors, a better model (internal predictivity) was observed using GasteigerHückel charges, but the PM3 method gave better external predictivity for 11 test compounds. For non-steroidal aromatase inhibitors related to fadrozole, Recanatini 6 observed similar models using either the AM1 method for geometry optimization and charge calculations or MAXIMIN2 molecular mechanics for geometry optimization and Gasteiger-Marsili charges. Navajas et al 7 verified that the mutagenic activity of 16 5H-furan-2-one derivatives was correlated with the LUMO field.…”

Modeling of diarylalkyl‐imidazole and diarylalkyl‐triazole derivatives as potent aromatase inhibitors for treatment of hormone‐dependent cancer

“…Field analysis studies have been performed on steroidal 8 and nonsteroidal 9 AIs, which revealed the importance of hydrophobicity for binding to the enzyme. Studies on flavone 10 and benzofuran 11 derivatives explored the importance of hydrogen bond acceptors with molecular hydrophobicity for inhibition of the enzyme.…”