Si Yan Liao

CoMFA and docking studies of 2-phenylindole derivatives with anticancer activity

Three-dimensional (3D) quantitative structure-activity relationship (QSAR) and docking studies of 43 tubulin inhibitors, 2-phenylindole derivatives with anticancer activity against human breast cancer cell line MDA-MB 231, have been carried out. The established 3D-QSAR model from the comparative molecular field analysis (CoMFA) in training set shows not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient value (R(2)=0.910) and cross-validation coefficient value (q(2)=0.705). Moreover, the predictive ability of the CoMFA model was further confirmed by a test set, giving the predictive correlation coefficient (R(2)(pred)) of 0.688. Based on the CoMFA contour maps and docking analyses, some key structural factors responsible for anticancer activity of this series of compounds were revealed as follows: the substituent R(1) should have higher electronegativity; the substituent R(2) should be linear alkyl with four or five carbon atoms in length; and the substituent R(3) should be selected to OCH(3)-kind group whereas should not be selected to CF(3)-kind group. Meanwhile, the interaction information between target and ligand was presented in detail. Such results can offer some useful theoretical references for understanding the action mechanism, designing more potent inhibitors and predicting their activities prior to synthesis.

Binding conformations and QSAR of CA-4 analogs as tubulin inhibitors

A theoretical study on the binding conformations and the quantitative structure–activity relationship (QSAR) of combretastatin A4 (CA-4) analogs as inhibitors toward tubulin has been carried out using docking analysis and comparative molecular field analysis (CoMFA). The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by the docking study; and a 3D-QSAR model showing significant statistical quality and satisfactory predictive ability was established, in which the correlation coefficient (R2) and cross-validation coefficient (q2) were 0.955 and 0.66, respectively. The same model was further applied to predict the pIC50 values for 16 congeneric compounds as external test set, and the predictive correlation coefficient R2pred reached 0.883. Other tests on additional validations further confirmed the satisfactory predictive power of the model. In this work, it was very interesting to find that the 3D topology structure of the active site of tubulin from the docking analysis was in good agreement with the 3D-QSAR model from CoMFA for this series of compounds. Some key structural factors of the compounds responsible for cytotoxicity were reasonably presented. These theoretical results can offer useful references for understanding the action mechanism and directing the molecular design of this kind of inhibitor with improved activity.

A DFT STUDY ON THE HYDROLYSIS MECHANISM OF THE NAMI-A-TYPE ANTITUMOR COMPLEX (HL)[trans-RUCl4L(dmso-S)](L=4-amino-1,2,4-triazole)

The hydrolysis process of Ru(III) complex (HL)[trans-RuCl4L(dmso-S)] (L=4-amino-1,2,4-triazole) (1), a potential antitumor complex similar to the well-known antitumor agent (ImH)[trans-RuCl4(dmso-S)(Im)](NAMI-A), was investigated using density functional theory (DFT) with the conductor-like polarizable continuum model (CPCM). The structural characteristics and the detailed energy profiles for the hydrolysis processes of this complex were obtained. For the first hydrolysis step, complex 1 with 4-amino-1,2,4-triazole ligand shows much faster aquation than NAMI-A with imidazole ligand and complex 2 with 4H-1,2,4-triazole ligand, and such a calculated result is in good agreement with the experimental one. For the second hydrolysis step, the formation of cis-diaqua products is found to be thermodynamically preferred over the trans isomers. In addition, on the basis of the analysis of electronic characteristics of species in the hydrolysis process, the trend in abilities (A) of hydrolysis products attacked nucleophilicly by pertinent biomolecules is revealed. These theoretical results will help in understanding the action mechanism of this potential Ru(III) drug with pertinent biomolecular targets.

QSAR AND ACTION MECHANISM OF TROXACITABINE PRODRUGS WITH ANTITUMOR ACTIVITY

The quantitative structure–activity relationship (QSAR) of troxacitabine prodrugs with antitumor activity has been studied by using the density functional theory (DFT), molecular mechanics (MM2), and statistical methods. The established QSAR model shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient and the square of the cross-validation coefficient (q2 = 0.807). The antitumor activity is expressed as pIC50, which is defined as the negative value of the logarithm of necessary molar concentration of a compound to cause 50% growth inhibition against the human non-small-cell lung cancer cell line SW1573. It appears to be mainly governed by two factors (or original variables), i.e. the calculated hydrophobic coefficient (C log P) of whole molecule and the net charges of the first atom of substituent R (QFR), although three descriptors, i.e. C log P, (C log P)2, and QFR, were selected in our multiple linear regression model. The factor C log P shows parabolic relation to pIC50 and its suitable range is around 5.6, and the other factor QFR shows a significant negative correlation with pIC50. In this paper, a detailed discussion on these two factors was carried out, and their close correlation with the action mechanism of these prodrugs was reasonably revealed. Such results can offer some useful theoretical references for understanding the action mechanism and directing the molecular design of this kind of compound with antitumor activity.

Binding Orientations, QSAR, and Molecular Design of Thiophene Derivative Inhibitors

A theoretical study on binding orientations and quantitative structure–activity relationship of thiophene derivatives as inhibitors towards tubulin has been carried out by using the docking analysis and the comparative molecular field analysis. The appropriate binding orientations and conformations of these compounds interacting with tubulin were revealed by docking study; and a 3D‐quantitative structure–activity relationship model showing significant statistical quality and satisfying predictive ability was established, in which the correlation coefficient (R2) and cross‐validation coefficient (q2) are 0.949 and 0.743, respectively. The same model was further applied to predict the pIC50 values for nine congeneric compounds as external test set, and the predictive correlation coefficient reaches 0.929, thus the predictive ability of this 3D‐quantitative structure–activity relationship model can be further confirmed. Some key structural factors of the compounds responsible for cytotoxicity were discussed in detail. Based on these structural factors, three new compounds with higher activity have been designed, and their cytotoxicities were also predicted by the established 3D‐quantitative structure–activity relationship model from comparative molecular field analysis as well as the docking analysis. We hope these theoretical results can be confirmed by experimental work.

2D/3D-QSAR STUDY ON ANALOGUES OF 2-METHOXYESTRADIOL WITH ANTICANCER ACTIVITY

Two-dimensional (2D) and three-dimensional (3D) quantitative structure–activity relationships (QSARs) of 23 analogs of 2-Methoxyestradiol with anticancer activity (expressed as pGI50) against MCF-7 human breast cancer cells have been studied by using a combined method of the DFT, MM2 and statistics for 2D, as well as the comparative molecular field analysis (CoMFA) for 3D. The established 2D-QSAR model in training set shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient and the square of the cross-validation coefficient (q2 = 0.779). The same model was further applied to predict pGI50 values of the four compounds in the test set, and the resulting being as high as 0.827, further confirms that this 2D-QSAR model has high predictive ability for this kind of compound. The 3D-QSAR model also shows good correlative and predictive capabilities in terms of R2(0.927) and q2(0.786) obtained from CoMFA model. The results that 2D- and 3D-QSAR analyses accord with each other, suggest that the electrostatic interaction plays a decisive role in determining the anticancer activity of the studied compounds, and that increasing the negative charge of substituent R2 and the positive charge of substituents linking to C17 as well as decreasing the size of substituent R1 are advantageous to improving the cytotoxicity. Such results can offer some useful theoretical references for directing the molecular design and understanding the action mechanism of this kind of compound with anticancer activity.

3D-QSAR STUDIES OF SUBSTITUTED 4-ARYL/HETEROARYL-4H-CHROMENES AS APOPTOSIS INDUCERS USING CoMFA AND CoMSIA

Three-dimensional (3D) quantitative structure–activity relationships (QSARs) of 36 apoptosis inducers, substituted 4-aryl/heteroaryl-4H-chromenes with anticancer activity against human breast cancer cell lines T47D, have been studied by using methods of comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA). The established 3D-QSAR models in training set show not only significant statistical quality, but also predictive ability, with high correlation coefficient (R2) values and cross-validation coefficient (q2) values: CoMFA (R2, q2: 0.944, 0.747), CoMSIA (R2, q2: 0.944, 0.704). Moreover, the predictive abilities of the CoMFA and CoMSIA models were further confirmed by a test set, giving the predictive correlation coefficients ( values) of 0.845 and 0.851, respectively. Based on the CoMFA and CoMSIA contour map analyses, some key factors responsible for anticancer activity of this series of compounds have been found as follows: the steric interaction plays a decisive role in determining the anticancer activities of these compounds; bulky groups as substituent R1 are not tolerated; in addition to a steric moderation, higher degree of electropositivity and hydrophobicity on the terminal alkyl of substituent R2 might be favorable to the activity; the substituent R3 should be hydrophobic; bulky and strong electron withdrawing groups for the substituent R4 are not advantageous to the activity; simultaneously introducing large electronegative atoms as hydrogen-acceptors to the first atoms of the substituents R5 and R6 may increase the activity, but substituents R5 and R6 with a linking group –OCH2O– may decrease the activity. Such results can offer some useful theoretical references for understanding the action mechanism, designing more potent derivatives, and predicting their activities prior to synthesis.