Conventional R2 Research Articles

Comparative molecular field analysis of a series of paclitaxel analogues.

A series of 94 paclitaxel analogues exhibiting antitumor activity by promoting the assembly of microtubules and inhibiting the disassembly process of microtubules to tubulin were investigated using the comparative molecular field analysis (CoMFA) method. These compounds belonging to 10 structural classes were randomly divided into a training set of 80 compounds and a test set of 14 compounds. Since the three-dimension structure of ligand--receptor complex is unknown, from X-ray and NMR data we rationally selected the three-dimension structure of paclitaxel in a polar solution as the active conformation and starting structure for molecule modeling, the other molecules were aligned using this molecule model as the template. The most optimal CoMFA yielded a two-components model, with significant cross-validation r2cv of 0.640 and conventional r2 of 0.868. The predictive ability of training set model was tested on the test set of 14 compounds. The tests not only revealed the robustness of the CoMFA model but demonstrated that for our model r2pred based on the mean activity of test set compounds can accurately estimate external predictivity but r2pred based on the mean activity of training set compounds overestimated the model. The CoMFA model explained why the activity of taxoid is sensitive to the stereochemistry of the atoms at C-2' and C-3' positions and the presence of hydroxyl group at C-2' position. The other factors affecting activity were also elucidated according to standard coefficient contour maps of steric and electrostatic fields derived from the CoMFA model.

Three-dimensional quantitative structure-activity relationship of melatonin receptor ligands: a comparative molecular field analysis study.

A three-dimensional quantitative structure-activity relationship using the comparative molecular field analysis (CoMFA) paradigm applied to 57 melatonin receptor ligands belonging to diverse structural families was performed. The compounds studied which have been synthesized previously and reported to be active at chicken brain melatonin receptors were divided into a training set of 48 molecules and a test set of 9 molecules. As most of these compounds have a highly flexible ethylamido side chain, the alignments were based on the most sterically constrained molecule which contains a tricyclic phenalene structure. This tricyclic compound can adopt an axial and an equatorial conformation. Two different molecular superpositions representing possible positioning within the receptor site have been suggested previously. CoMFA was tentatively used to discriminate between alternate hypothetical biologically active conformation and between possible positionings. The best 3D quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.798, 0.967, and 0.76, respectively, along with an average absolute error of prediction of 0.25 log units. These results suggest that the active conformation of the most flexible molecules including melatonin is in a folded form if we consider the spatial position of the ethylamido side chain relative to the aromatic ring.

Derivation of a 3D pharmacophore model for the angiotensin-II site one receptor.

A systematic search has been used to derive a hypothesis for the receptor-bound conformation of A-II antagonists at the AT1 receptor. The validity of the pharmacophore hypothesis has been tested using CoMFA, which included 50 diverse A-II antagonists, spanning four orders of magnitude in activity. The resulting cross-validated R2 of 0.64 (conventional R2 of 0.76) is indicative of a good predictive model of activity, and has been used to estimate potency for a variety of non-peptidyl antagonists. The structural model for the non-peptide has been compared with respect to the natural substrate, A-II, by generating peptide to non-peptide overlays.

3‐D QSAR for intrinsic activity of 5‐HT1A receptor ligands by the method of comparative molecular field analysis

AbstractThe affinity of a ligand for a receptor is usually expressed in terms of the dissociation constant (Ki) of the drug‐receptor complex, conveniently measured by the inhibition of radioligand binding. However, a ligand can be an antagonist, a partial agonist, or a full agonist, a property largely independent of its receptor affinity. This property can be quantitated as intrinsic activity (1A), which can range from 0 for a full antagonist to 1 for a full agonist. Although quantitative structure–activity relationship (QSAR) methods have been applied to the prediction of receptor affinity with considerable success, the prediction of IA, even qualitatively, has rarely been attempted. Because most traditional QSAR methods are limited to congeneric series, and there are often major structural differences between agonists and antagonists, this lack of success in predicting IA is understandable. To overcome this limitation, we used the method of comparative molecular field analysis (CoMFA), which, unlike traditional Hansch analysis, permits the inclusion of structurally dissimilar compounds in a single QSAR model. A structurally diverse set of 5‐hydroxytryptamine1A (5‐HT1A) receptor ligands, with literature IA data (determined by the inhibition of 5‐HT sensitive forskolin‐stimulated adenylate cyclase), was used to develop a 3‐D QSAR model correlating intrinsic activity with molecular structure properties of 5HT1A receptor ligands. This CoMFA model had a crossvalidated r2 of 0.481, five components and final conventional r2 of 0.943. The receptor model suggests that agonist and antagonist ligands can share parts of a common binding site on the receptor, with a primary agonist binding region that is also occupied by antagonists and a secondary binding site accommodating the excess bulk present in the sidechains of many antagonists and partial agonists. The CoMFA steric field graph clearly shows that agonists tend to be “flatter” (more coplanar) than antagonists, consistent with the difference between the 5‐HT1A agonist and antagonist pharmacophores proposed by Hibert and coworkers. The CoMFA electrostatic field graph suggests that, in the region surrounding the essential protonated aliphatic amino group, the positive molecular electrostatic potential may be weaker in antagonists as compared to agonists. Together, the steric and electrostatic maps suggest that in the secondary binding site region increased hydrophobic binding may enhance antagonist activity. These results demonstrate that CoMFA is capable of generating a statistically crossvalidated 3‐D QSAR model that can successfully distinguish between agonist and antagonist 5‐HT1A ligands. To the best of our knowledge, this is the first time this or any other QSAR method has been successfully applied to the correlation of structure with IA rather than potency or affinity. The analysis has suggested various structural features associated with agonist and antagonist behaviors of 5‐HT1A ligands and thus should assist in the future design of drugs that act via 5‐HT1A receptors. © 1993 John Wiley & Sons, Inc.