Three-dimensional Quantitative Structure-activity Relationship Analysis Research Articles

Nematocidal quassinoids and bicyclophosphorothionates: a possible common mode of action on the GABA receptor

The present study was undertaken to identify noncompetitive γ-aminobutyric acid receptor (GABAR) antagonists that are effective in nematodes, as well as to examine the hypothesis that the noncompetitive antagonism of the GABAR underlies the nematocidal activity of quassinoids against free-living nematodes of the Diplogastridae family. First, 14 known GABAR antagonists were screened for the effectiveness of their nematocidal activity in Diplogastridae. As a result, 3-isopropyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane 1-sulfides (3-isopropyl-BPTs) were found to have high nematocidal activities, and 4-cyclohexyl-3-isopropyl-BPT ( 23) and 3-isopropyl-4-(2-propenyl)-BPT ( 27) were the two most potent analogues; these compounds are equipotent to samaderine B and more potent than the anthelmintic abamectin. 23-resistant nematodes, selected by challenge with 23, showed cross-resistance to samaderine B. 23 (10 μM) reduced [ 3H] 23 binding to nematode membranes by 30.4%. Samaderine B (10 μM) resulted in a similar level of the inhibition, but had neither additive nor synergistic effects on the 23 inhibition of [ 3H] 23 binding. These findings suggest that samaderine B shares a common binding site with the GABAR antagonist 23 in Diplogastridae. The results of comparative molecular field analysis, a method of three-dimensional quantitative structure–activity relationship analysis, supported this conclusion.

Three-dimensional quantitative structure–activity relationship analyses of piperidine-based CCR5 receptor antagonists

The CCR5 chemokine receptor has recently been found to play a crucial role in the viral entry stage of HIV infection and has therefore become an attractive potential target for anti-HIV therapeutics. On the other hand, the lack of CCR5 crystal structure data has impeded the development of structure-based CCR5 antagonist design. In this paper, we compare two three-dimensional Quantitative Structure–Activity Relationship (3D-QSAR) methods: Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) on a series of piperidine-based CCR5 antagonists as an alternative approach to investigate the interaction between CCR5 antagonists and their receptor. Superimposition of antagonist structures was performed using two alignment rules: atomic/centroid rms fit and rigid body field fit techniques. The 3D QSAR models were derived from a training set of 72 compounds, and were found to have predictive capability for a set of 19 holdout test compounds. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to biological activity in this series of compounds. Further analyses of these interaction-field contour maps also showed a high level of internal consistency.

Three-dimensional quantitative structure-activity relationship analyses of peptide substrates of the mammalian H+/peptide cotransporter PEPT1.

The utilization of the carrier protein PEPT1 for the absorption of peptidomimetic drug molecules is a promising strategy for oral drug administration and increasing bioavailability. In the absence of structural information on the binding mode of substrates to PEPT1, a computational study was conducted to explore the structural requirements for substrates and to derive a predictive model that may be used for the design of novel orally active drugs. A comparative molecular field analysis (CoMFA) and a comparative molecular similarity indices analysis (CoMSIA) were performed on a series of 79 dipeptide-type substrates for which affinity data had been collected in a single test system under the same conditions. These studies produced models with conventional r(2) and cross-validated coefficient (q(2)) values of 0.901 and 0.642 for CoMFA and 0.913 and 0.776 for CoMSIA. The models were validated by an external test set of 19 dipeptides and dipeptide derivatives. CoMSIA contour maps were used to identify the recognition elements that are relevant for the binding of PEPT1 substrates. The 3D QSAR models provide an insight in the interactions between substrates and PEPT1 on the molecular level and allow the prediction of affinity constants of new compounds.

Three-dimensional quantitative structure-activity relationship analysis of propafenone-type multidrug resistance modulators: influence of variable selection on test set predictivity.

An extended set of multidrug-resistance modulators of the propafenone type were investigated using CoMFA and CoMSIA. A number of 3D-QSAR models were derived from steric, electrostatic, and hydrophobic fields and their combinations. The hydrophobic fields alone and in combination with the steric and both (steric and electrostatic) fields yielded the models with the highest cross-validated predictivity, in agreement with a previous analysis of a smaller data set of propafenone-type multidrug-resistance (MDR) modulators. Inclusion of lipophilicity did not lead to an improvement of the models. The results point to the importance of hydrophobicity as a space-directed molecular property for MDR-modulating activity. The influence of variable selection applying the GOLPE procedure was investigated with an external test set. Variable-selection procedure was repetitively applied, keeping at each stage variables with uncertain contribution to the models. For the CoMFA-based 3D-QSAR models, an increase in external prediction quality was found. In contrast, the CoMSIA-based 3D-QSAR models were not improved by the GOLPE variable-selection procedure.

Synthesis and Three-Dimensional Quantitative Structure-Activity Relationship Analysis of H3 Receptor Antagonists Containing a Neutral Heterocyclic Polar Group

Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H(3) receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H(3) receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H(3) receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H(3) receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H(3) receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.

Three‐dimensional Quantitative Structure‐Activity Relationship Analyses of a Series of Butenolide ETA Antagonists

AbstractTwo kinds of Three‐dimensional Quantitative Structure‐activity Relationship (3D‐QSAR) methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were applied to analyze the structure‐activity relationship of a series of 63 butenolide ETA selective antagonists with respect to their inhibition against human ETA receptor. The CoMFA and CoMSIA models were developed for the conceivable alignment of the molecules based on a template structure from the crystallized data. The statistical results from the initial orientation of the aligned molecules show that the 3D‐QSAR model from CoMFA (q2 = 0.543) is obviously superior to that from the conventional CoMSIA (q2 = 0.407). In order to refine the model, all‐space search (ASS) was applied to minimize the field sampling process. By rotating and translating the molecular aggregate within the grid systematically, all the possible samplings of the molecular fields were tested and subsequently the one with the highest q2 was picked out. The comparison of the sensitivity of CoMFA and CoMSIA to different space orientation shows that the CoMFA q2 values are more sensitive to the translations and rotations of the aligned molecules with respect to the lattice than those of CoMSIA. The best CoMFA model from ASS was further refined by the region focused technique. The high quality of the best model is indicated by the high cross‐validated correlation and the prediction on the external test set. The CoMFA coefficient contour plots identify several key features that explain the wide range of activities, which may help us to design new effective ETA selective antagonists.

Synthesis and Three-Dimensional Quantitative Structure-Activity Relationship Analysis of H3 Receptor Antagonists Containing a Neutral Heterocyclic Polar Group

Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was applied to a series of H3receptor antagonists characterized by an imidazole ring, an alkyl spacer, and a heterocyclic polar moiety containing an imidazole or a thiazole ring, with a view to investigate the requirements for H3receptor affinity on rat cortex membranes. The compounds were aligned based on the hypothesis that the presence of a H-bond donor group in the polar portion of the molecule can increase H3receptor affinity. The 3D-QSAR analysis, which was performed using both the CoMFA and CoMSIA protocols, revealed that the presence of a H-bond donor group is not statistically relevant for H3receptor affinity. Based on this result, another alignment was adopted that took into consideration the structural features common to all compounds, namely the imidazole ring and the N atom with a free lone pair in the polar portion. The 3D-QSAR models thus obtained showed that H3receptor affinity is modulated by the position and direction of the intermolecular interaction elicited by the polar group in the ligands.

Quantitative structure-activity relationship (QSAR) and three-dimensional QSAR analysis of a series of xanthates as inhibitors and inactivators of cytochrome P450 2B1

1. Various xanthates (R-OCS2) were found to be mechanism-based inactivators of cytochrome P450 2B1 (CYP2B1) and CYP2B6 via formation of reactive metabolites. 2. In the present study, quantitative structure-activity relationships (QSARs) were derived with inhibitory and inactivation potencies of 15 xanthates (R = two to 20 methylene groups, allyl, cyclohexyl or O -tricyclo[5.2.1.0 2,6] dec-9-yl (D609)) against purified, reconstituted rat liver CYP2B1. Factor, regression and comparative molecular field analyses (CoMFA) were used. 3. The compounds formed two groups whose activities depended on different structural features: the first group consisted of compounds with ethyl, propyl, allyl, cyclohexyl and D609 substituents; the second involved compounds with eight to 20 methylene groups. 4. High correlation between the molecular volume and inhibitory potency of the xanthates of the second group was found. The inactivation potency in the first group correlated with the charge of the first carbon atom of R, identifying this atom as a potential target for metabolic attack. A decrease in the inactivation potency with an increase in the size of R was observed in the second group. This finding could be explained by a decreased rate of metabolism of the long alkyl chain compounds and/or by difficulty in binding of the resulting metabolite(s) to the enzyme molecule.

Three-dimensional quantitative structure–activity relationship analyses of a series of cinnamamides

A 3D-QSAR study was conducted on a series of cinnamamides with anticonvulsant activities using comparative molecular similarity indices analysis (CoMSIA) and comparative molecular field analysis (CoMFA). In the current work, all-space searching procedure was applied to minimize the field sampling process. The comparison of sensitivity of CoMFA and CoMSIA to the different space orientation showed that the CoMSIA q 2 values were less sensitive to the translations and rotations of the aligned molecules with respect to the lattice compared with CoMFA. After all-space searching calculations, we could come up with a good CoMSIA model ( q 2 and r 2 values equal to 0.742 and 0.917, respectively) and the validity of the model was confirmed by additional five compounds in the external test set. Contour surfaces for the molecular fields are presented. These results provide useful information in the characterization and identification of the potential mechanisms of intermolecular interactions between ligand and receptor.

Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homology modeling, and three-dimensional quantitative structure-activity relationship analysis.

This study describes the generation of a three-dimensional quantitative structure activity relationship (3D-QSAR) model for 29 structurally diverse, competitive CYP2C9 inhibitors defined experimentally from an initial data set of 73 compounds. In parallel, a homology model for CYP2C9 using the rabbit CYP2C5 coordinates was built. For molecules with a known interaction mode with CYP2C9, this homology model, in combination with the docking program GOLD, was used to select conformers to use in the 3D-QSAR analysis. The remaining molecules were docked, and the GRID interaction energies for all conformers proposed by GOLD were calculated. This was followed by a principal component analysis (PCA) of the GRID energies for all conformers of all compounds. Based on the similarity in the PCA plot to the inhibitors with a known interaction mode, the conformer to be used in the 3D-QSAR analysis was selected. The compounds were randomly divided into two groups, the training data set (n = 21) to build the model and the external validation set (n = 8). The PLS (partial least-squares) analysis of the interaction energies against the K(i) values generated a model with r(2) = 0.947 and a cross-validation of q(2) = 0.730. The model was able to predict the entire external data set within 0.5 log units of the experimental K(i) values. The amino acids in the active site showed complementary features to the grid interaction energies in the 3D-QSAR model and were also in agreement with mutagenesis studies.

Three-dimensional quantitative structure-activity relationship analysis of acyclic and cyclic chloronicotinyl insecticides

The binding activity of chloronicotinyl insecticides, including acetamiprid, nitenpyram and related compounds, to the nicotinic acetylcholine receptors (nAChR) of houseflies was measured. These compounds were defined as ‘acyclic’ compounds. Variations in the binding activity were analysed using comparative molecular field analysis (CoMFA) which is a technique for the analysis of three-dimensional quantitative structure–activity relationships. The CoMFA results showed that steric interactions were more significant for the acyclic compounds than for imidacloprid and its derivatives (cyclic compounds). It was also shown that the acyclic compounds could bind to housefly-nAChR in a similar manner to the cyclic compounds, and that the electrostatic natures of the acyclic amino- and cyclic imdazolidine-moieties affected their binding activity. © 2000 Society of Chemical Industry

Three-Dimensional quantitative structure–Activity relationship analyses of RGD mimetics as fibrinogen receptor antagonists

In order to better understand the structural requirements of fibrinogen receptor antagonists, variations in the platelet aggregation inhibitory activity of a series of RGD mimetics were examined using techniques for the analysis of three-dimensional quantitative structure–activity relationship, such as CoMFA.

A strategy for the incorporation of water molecules present in a ligand binding site into a three-dimensional quantitative structure--activity relationship analysis.

Water present in a ligand binding site of a protein has been recognized to play a major role in ligand-protein interactions. To date, rational drug design techniques do not usually incorporate the effect of these water molecules into the design strategy. This work represents a new strategy for including water molecules into a three-dimensional quantitative structure-activity relationship analysis using a set of glucose analogue inhibitors of glycogen phosphorylase (GP). In this series, the structures of the ligand-enzyme complexes have been solved by X-ray crystallography, and the positions of the ligands and the water molecules at the ligand binding site are known. For the structure-activity analysis, some water molecules adjacent to the ligands were included into an assembly which encompasses both the inhibitor and the water involved in the ligand-enzyme interaction. The mobility of some water molecules at the ligand binding site of GP gives rise to differences in the ligand-water assembly which have been accounted for using a simulation study involving force-field energy calculations. The assembly of ligand plus water was used in a GRID/GOLPE analysis, and the models obtained compare favorably with equivalent models when water was excluded. Both models were analyzed in detail and compared with the crystallographic structures of the ligand-enzyme complexes in order to evaluate their ability to reproduce the experimental observations. The results demonstrate that incorporation of water molecules into the analysis improves the predictive ability of the models and makes them easier to interpret. The information obtained from interpretation of the models is in good agreement with the conclusions derived from the structural analysis of the complexes and offers valuable insights into new characteristics of the ligands which may be exploited for the design of more potent inhibitors.