QSAR of apoptosis induction in various cancer cells

In continuing our QSAR study of apoptosis, we consider in this report the action of phenolic compounds on Ramos cells (non-Hodgkins B-cell lymphoma): the effect of O-8-thapsigargin analogues on human prostate cancer cells, Tsu-Pr-1 and the induction of apoptosis of a complex set of congeners on human fibrosarcoma cells HT 1080. The human prostate cancer cells activity is very similar to that of the Ramos cells. While the QSAR for the fibrosarcoma cells resembles that of our earlier study with L1210 leukemia cells. The two different types of QSAR suggest at least two quite different types of receptors for the induction of apoptosis.     

Pharmacophore, QSAR, and ADME based semisynthesis and in vitro evaluation of ursolic acid analogs for anticancer activity

In the present work, QSAR models for predicting the activities of ursolic acid analogs against human lung (A-549) and CNS (SF-295) cancer cell lines were developed by a forward stepwise multiple linear regression method using a leave-one-out approach. The regression coefficient (r(2)) and the cross-validation regression coefficient (rCV(2)) of the QSAR model for cytotoxic activity against the human lung cancer cell line (A-549) were 0.85 and 0.80, respectively. The QSAR study indicated that the LUMO energy, ring count, and solvent-accessible surface area were strongly correlated with anticancer activity. Similarly, the QSAR model for cytotoxic activity against the human CNS cancer cell line (SF-295) also showed a high correlation (r(2) = 0.99 and rCV(2) = 0.96), and indicated that dipole vector and solvent-accessible surface area were strongly correlated with activity. Ursolic acid analogs that were predicted to be active against these cancer cell lines by the QSAR models were semisynthesized and characterized on the basis of their (1)H and (13)C NMR spectroscopic data, and were then tested in vitro against the human lung (A-549) and CNS (SF-295) cancer cell lines. The experimental results obtained agreed well with the predicted values.     

QSAR studies on the activation of the human carbonic anhydrase cytosolic isoforms I and II and secretory isozyme VI with amino acids and amines

The first QSAR study on the activation of the human secretory isoform of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA VI, with a series of amines and amino acids is reported. A large set of topological indices have been used to obtain several tri-/tetra-parametric models. We compared the CA VI activating QSAR models with those calculated for activation of the cytosolic human isozymes hCA I and hCA II. In addition, the effect of D- and L-amino acids as activators of hCA I, hCA II and of hCA VI as compared to those of structurally related biogenic amines was investigated for obtaining statistically significant and predictive QSAR equations. The obtained models are discussed using a variety of statistical parameters. The best models were obtained for hCA II activation, followed by hCA I, whereas the QSAR models for the activation of hCA VI were statistically weaker.     

QSAR of anticancer compounds. Bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides)

QSAR have been developed for the anticancer activity (growth inhibition) of various tumor cells by bis(11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides), bis(phenazine-1-carboxamides), and bis(naphthalimides). Of the seven QSAR, positive hydrophobic interactions are found in only two examples: bis(naphthalimides) versus human colon cancer cells. This is consistent with other QSAR of anticancer compounds where hydrophobic interactions are found to be unimportant.     

QSAR studies and pharmacophore identification for arylsubstituted cycloalkenecarboxylic acid methyl esters with affinity for the human dopamine transporter

Data from a series of 29 monoamine transport inhibitors were used to generate 2D and 3D QSAR models for their binding affinity to the human dopamine transporter (hDAT). Among the inhibitors were many non-nitrogen containing compounds. The 2D QSAR analysis resulted in the equation -logK(i)=4.00-3.93E(LUMO)-0.67E(HOMO)-3.24sigma(p), which predicted the importance of electron withdrawing groups in the aromatic moiety. However, the model failed to predict the observed poor binding of nitro-substituted compounds. In contrast, a derived 3D QSAR model was capable of predicting these more correctly.     

Quantitative structure-activity relationship (QSAR) for neuroprotective activity of terpenoids

Neuroprotective activity of thirteen terpenoids on human neuroblastoma SH-SY5Y was evaluated in vitro by using a simulated ischemia model. The protective effects on ischemic damage ranged from 3.0% to 56.5%, and trans-4,11,11-trimethyl-8-methylenebicyclo[7,2,0]undec-4-ene (trans-caryophyllene) showed the highest neuroprotective activity. A quantitative structure-activity relationship (QSAR) model was developed for eleven terpenoids with significant neuroprotective activity using TSAR software. The QSAR study produced two equations with significant predictive values (r(2) and p value) and indicated that the activity was mainly governed by lipophilicity, shape index, and electrostatic property. This QSAR approach can contribute to a better understanding of structural properties of the terpenoids responsible for neuroprotection, and can be useful in predicting the neuroprotective activity of other terpenoids.     

Quantitative structure-activity relationships and the prediction of MHC supermotifs

The underlying assumption in quantitative structure-activity relationship (QSAR) methodology is that related chemical structures exhibit related biological activities. We review here two QSAR methods in terms of their applicability for human MHC supermotif definition. Supermotifs are motifs that characterise binding to more than one allele. Supermotif definition is the initial in silico step of epitope-based vaccine design. The first QSAR method we review here--the additive method--is based on the assumption that the binding affinity of a peptide depends on contributions from both amino acids and the interactions between them. The second method is a 3D-QSAR method: comparative molecular similarity indices analysis (CoMSIA). Both methods were applied to 771 peptides binding to 9 HLA alleles. Five of the alleles (A*0201, A*0202, A*0203, A*0206 and A*6802) belong to the HLA-A2 superfamily and the other four (A*0301, A*1101, A*3101 and A*6801) to the HLA-A3 superfamily. For each superfamily, supermotifs defined by the two QSAR methods agree closely and are supported by many experimental data.     

Prediction of HIV-1 protease inhibitory activity of 4-hydroxy-5,6-dihydropyran-2-ones: QSAR study

Inhibition of human immunodeficiency virus 1 (HIV-1) protease is an important strategy for the treatment of HIV and acquired immune deficiency syndrome (AIDS). Therefore, HIV-1 protease inhibitory activity of dihydropyranone derivatives has been analyzed with different physico-chemical parameters. In the present work, QSAR studies were performed on a series of 4-hydroxy-5,6-dihydropyran-2-ones to explore the physico-chemical parameters responsible for their HIV-1 protease inhibitory activity. Physico-chemical parameters were calculated using WIN CAChe 6.1. Stepwise multiple linear regression analysis was performed to derive QSAR models which were further evaluated for statistical significance and predictive power by internal and external validation. The selected best QSAR model was having correlation coefficient (R)?=?0.875 and cross-validated squared correlation coefficient (Q²)?=?0.707. The developed significant QSAR model indicates that hydrophobicity of whole molecule and the substituent present at sixth position of dihydropyranones play an important role in the HIV-1 protease inhibitory activities of 4-hydroxy-5,6-dihydropyran-2-ones.     

QSAR analyses on ginkgolides and their analogues using CoMFA, CoMSIA, and HQSAR

Ginkgolides, isolated from ginkgo balba leaves, were found to be powerful as natural antagonists of human platelet activating factor (PAF) in treatment of some diseases such as acute inflammation, tissue rejection, asthma, and ischemic injury. Ginkgolides have a cage skeleton consisting of six five-membered rings, therefore, are very tough to be synthesized. For finding new powerful substitutes of the natural ginkgolides for treating those diseases, three methods, viz. CoMFA, CoMSIA, and HQSAR, were used to investigate the relationship between 117 ginkgolide analogues with great structural diversity and their bioactivities against PAF receptor. The high q2 released from the different QSAR methods, ranging from 0.583 to 0.684, suggests that three rational and predictive QSAR models were successfully built. These models also show clearly how steric, electrostatic, hydrophobicity, and individual atom affect molecular bioactivity as antagonists of PAF. These results could also be used to account for the unusually higher bioactivity of ginkgolide B than other ginkgolides. The possible binding mechanism between ginkgolides and human PAF receptor was also deduced based on the QSAR models. Therefore, this study should be very helpful in discovering new drugs as PAF antagonists in fighting against various diseases related to PAF and PAF receptor.     

Structure-activity relationships for halobenzene induced cytotoxicity in rat and human hepatocytes

Halobenzenes are ubiquitous environmental contaminants, which are hepatotoxic in both rodents and humans. The molecular mechanism of halobenzene hepatotoxicity was investigated using Quantitative structure-activity relationships (QSAR) and accelerated cytotoxicity mechanism screening (ACMS) techniques in rat and human hepatocytes. The usefulness of isolated hepatocytes for prediciting in vivo xenobiotic toxicity was reassessed by correlating the LC(50) of 12 halobenzene congeners in phenobarbital (PB) induced rat hepatocytes in vitro determined by ACMS to the hepatotoxicities reported in vivo in PB-induced male Sprague-Dawely (SD) rats. A high correlation (r(2)=0.90) confirmed the application of hepatocytes as a "gold standard" for toxicity testing in vitro. QSARs were derived to determine the physico-chemcial variables that govern halobenzene toxicity in PB-induced rat, normal rat and human hepatocytes. We found that toxicity in normal rat and normal human hepatocytes both strongly correlate with hydrophobicity (logP), ease of oxidation (E(HOMO), energy of the highest molecular orbital) and on the asymmetric charge distribution according to arrangement of halogen substituents (dipole moment, mu). This suggests that halobenzene interaction with cytochrome P450 for oxidation is the metabolic activating path for toxicity and is similar in both species. In PB-induced rat hepatocytes the QSAR derivation is changed, where halobenzene toxicity strongly correlates to logP and dipole moment, but not E(HOMO). The changed QSAR suggests that oxidation is no longer the rate-limiting step in the cytotoxic mechanism when CYP2B/3A levels are increased, confirming CYP450 oxidation as the metabolic activating step under normal conditions.     

Development of multiple QSAR models for consensus predictions and unified mechanistic interpretations of the free-radical scavenging activities of chromone derivatives

Antioxidants are important defenders of the human body against nocive free radicals, which are the causative agents of most life-threatening diseases. The immense biomedicinal utility of antioxidants necessitates the development and design of new synthetic antioxidant molecules. The present report deals with the modeling of a series of chromone derivatives, which was done to provide detailed insight into the main structural fragments that impart antioxidant activity to these molecules. Four different quantitative structure–property relationship (QSAR) techniques, namely 3D pharmacophore mapping, comparative molecular similarity indices analysis (CoMSIA 3D-QSAR), hologram QSAR (HQSAR), and group-based QSAR (G-QSAR) techniques, were employed to obtain statistically significant models with encouraging external predictive potentials. Moreover, the visual contribution maps obtained for the different models signify the importance of different structural features in specific regions of the chromone nucleus. Additionally, the G-QSAR models determine the composite influence of pairs of substituent fragments on the overall antioxidant activity profiles of the molecules. Multiple models with different strategies for assessing structure–activity relationships were applied to reach a unified conclusion regarding the antioxidant mechanism and to provide consensus predictions, which are more reliable than values derived from a single model. The structural information obtained from the various QSAR models developed in the present work can thus be effectively utilized to design and predict the activities of new molecules belonging to the class of chromone derivatives.     

The 3-D QSAR study of anticancer 1-N-substituted imidazo- and pyrrolo-quinoline-4,9-dione derivatives by CoMFA and CoMSIA

The 3-D QSAR analysis with new imidazo- and pyrrolo-quinolinedione derivatives was conducted by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). When crossvalidation value (q(2)) is 0.844 at four components, the Pearson correlation coefficient (r(2)) of the CoMFA is 0.964. In the CoMSIA, q(2) is 0.709 at six components and r(2) is 0.969. Unknown samples were analyzed, using QSAR analyzed results from the CoMFA and CoMSIA methods. Excellent agreement was obtained between, with an error range of 0.01-0.15 the calculated values and measured in vitro cytotoxic activities against human lung A-549 cancer cell lines.     

Mechanism of toxicity of esters of caffeic and dihydrocaffeic acids

Ten esters each of caffeic acid and dihydrocaffeic acid have recently been synthesized. Cytotoxicity evaluations of these esters versus L1210 leukemia and MCF-7 breast cancer cells in culture have led to the delineation of substantially different QSAR for each series. The L1210 QSAR for dihydrocaffeic acid esters resembles the QSAR obtained for simple phenols and estrogenic phenols. However, the QSAR pertaining to the caffeic acid esters differs considerably from its sister QSAR. This difference may be attributed to the presence of the olefinic linkage in the side chain. The octyl ester of caffeic acid is nearly ten times as toxic to the leukemia cells than the widely studied phenethyl ester, CAPE.     

Quantitative structure-activity relationships (QSARs) for inhibitors and substrates of CYP2B enzymes: importance of compound lipophilicity in explanation of potency differences

The results of quantitative structure-activity relationship (QSAR) studies on inhibitors and substrates of cytochrome P450 2B (CYP2B) subfamily enzymes are reported. It was found that lipophilicity (in the form of log P) is the most important property for explaining the variations in inhibitory activity, and there are similarities between QSARs for both substrates and inhibitors for CYP2B6 (human), and also between those of other CYP2B enzymes, such as CYP2B1 (rat) and CYP2B4 (rabbit). Both linear and quadratic lipophilicity relationships are evidenced in human and other mammalian species, and the particular type of expression found is probably due to the nature of the compounds under investigation, as it is usually the homologous series which tend to show quadratic relationships in log P. The findings from QSAR studies can be rationalized by molecular modelling of the active site interactions with both P450 crystal structures and homology models of CYP2B subfamily enzymes.