CoMSIA Analyses Research Articles

CoMFA, CoMSIA, HQSAR and Molecular Docking Analysis of Ionone-based Chalcone Derivatives as Antiprostate Cancer Activity.

Androgen receptor has been proved to be effective site for treatment of prostate cancer. Molecular modeling methods performed on forty-three ionone based chalcones derivatives as anti-prostate cancer activity. The designed comparative molecular field analysis, comparative similarity indices analysis and hologram quantitative structure activity relationship models produced statistically significant results with the cross-validated correlation coefficients (q(2)) of 0.527, 0.550 and 0.670, non-cross-validated correlation coefficients (r(2)) 0.636, 0.671 and 0.746 and predicted r(2) (Pred r(2)) of 0.621, 0.563 and 0.732, respectively. Furthermore, bioactive conformation was explored and explained by docking of the potent compound 25 into the binding site of androgen receptor. Present study deals with comparative molecular field analysis, comparative similarity indices analysis and hologram quantitative structure activity relationship and molecular docking studies of the ionone-based chalcones and their derivatives, obtained from literature. The model obtained could be effectively used as a channeling tool for further structure modification and designing of some novel potent anti-prostate cancer compounds.

A combined CoMFA and CoMSIA 3D-QSAR study of benzamide type antibacterial inhibitors of the FtsZ protein in drug-resistant Staphylococcus aureus

A major problem today is bacterial resistance to antibiotics and the small number of new therapeutic agents approved in recent years. The development of new antibiotics capable of acting on new targets is urgently required. The filamenting temperature-sensitive Z (FtsZ) bacterial protein is a key biomolecule for bacterial division and survival. This makes FtsZ an attractive new pharmacological target for the development of antibacterial agents. There have been several attempts to develop ligands able to inhibit FtsZ. Despite the large number of synthesized compounds that inhibit the FtsZ protein, there are no quantitative structure–activity relationships (QSAR) that allow for the rational design and synthesis of promising new molecules. We present the first 3D-QSAR study of a large and diverse set of molecules that are able to inhibit the FtsZ bacterial protein. We summarize a set of chemical changes that can be made in the steric, electrostatic, hydrophobic and donor/acceptor hydrogen-bonding properties of the pharmacophore, to generate new bioactive molecules against FtsZ. These results provide a rational guide for the design and synthesis of promising new antibacterial agents, supported by the strong statistical parameters obtained from CoMFA (r2pred = 0.974) and CoMSIA (r2pred = 0.980) analyses.

Bioactive conformation analysis of anthranilic diamide insecticides: DFT-based potential energy surface scanning and 3D-QSAR investigations

Abstract Anthranilic diamides are fasting growing class insecticides in modern crop protection for their high activity, low ecotoxicity, and broad insecticidal spectra. However, the bioactive conformations of anthranilic diamides are still unclear until now. In the present study, DFT-based potential energy surface scanning was used to detect the low energy conformations of chlorantraniliprole, then were used respectively in the structure alignment for a series of anthranilic diamide compounds followed by detailed CoMFA and CoMSIA analyses. Finally, the bioactive conformations of anthranilic diamide insecticides were revealed from a series of low energy conformations, which might provide some clues for future insecticide design.

Predictive 3D-QSAR and HQSAR model generation of isocitrate lyase (ICL) inhibitors by various alignment methods combined with docking study

Isocitrate lyase (ICL) is one of the most important targets in the treatment of Mycobacterium tuberculosis. In this study a diverse set of 2-benzanilide derivatives were aligned by two different methods for CoMFA, CoMSIA, and HQSAR analysis. The best CoMFA model was obtained with the internal validation value (q2) of 0.730 and conventional coefficient (r2) of 0.944. Various CoMSIA models were generated and cross-validated. The best cross-validation coefficient (q2) value was found to be statistically satisfactory (0.688). Both the models were validated by test set of 10 compounds with satisfactory prediction value of (r2pred) 0.725 and 0.631 for CoMFA and CoMSIA, respectively. Cross-validation coefficient value (q2) of 0.694 and r2 of 0.856 were obtained for HQSAR study. The docking study reveals that large hydrophobic pockets occupy R substitutions of these compounds. An electronically negative surface is observed near R1 substitution. The results of the 3D-QSAR analysis corroborate with the molecular docking results, and our findings will serve as a basis for further development of better allosteric inhibitors of ICL inhibitors against M. tuberculosis.

3D QSAR and HQSAR analysis of protein kinase B (PKB/Akt) inhibitors using various alignment methods

Protein kinase B (PKB/Akt) regulates all aspects of cell growth, differentiation, and division. PKB/Akt has recently garnered a great deal of attention as a promising molecular target for cancer therapy due to its involvement in the development of several human cancers. In this study a diverse set of 56 Akt1 inhibitors were aligned by three different methods (pharmacophore-, docking-based and rigid body alignment) for CoMFA, CoMSIA and HQSAR analysis. The best QSAR models were obtained using rigid body alignment (Distill). CoMFA and CoMSIA models were found statistically significant with leave-one-out correlation coefficient (q2) of 0.627 and 0.598, respectively, cross validated coefficient (rcv2) of 0.644 and 0.563, respectively, and conventional coefficient (r2) of 0.867 and 0.865, respectively. QSAR models were validated by a test set of 9 compounds giving satisfactory predicted correlation coefficient (rpred2) of 0.603 and 0.613 for CoMFA and CoMSIA models, respectively. Leave-one-out correlation value (q2) of 0.687, rpred2 of 0.742 and r2 of 0.868 were obtained for HQSAR analysis and found satisfactory. This study provides valuable clues to design new compounds against PKB/Akt.

CoMFA and CoMSIA analysis of protein kinase B (PKBβ) inhibitors using various alignment methods

Protein kinase B (PKB) is considered as a key mediator of proliferation and survival pathways, which involved in the development of several human cancers. PKB is a recognized target for the development of small-molecule inhibitors for the treatment of cancer. In this study a diverse set of 73 PKBβ inhibitors were aligned by three different methods (pharmacophore, docking-based, and rigid body alignment) for CoMFA and CoMSIA analysis. The best 3D QSAR models were obtained using pharmacophore-based alignment. CoMFA and CoMSIA models were found statistically significant with leave-one-out correlation coefficients (q2) of 0.613 and 0.562 respectively, cross-validated coefficients (r2cv) of 0.609 and 0.558, respectively and conventional coefficients (r2) of 0.914 and 0.989, respectively. 3D QSAR models were validated by a test set of 12 compounds giving satisfactory predicted correlation coefficients (r2pred) of 0.767 and 0.622 for CoMFA and CoMSIA models, respectively. This study provides valuable clues to design new compounds against PKBβ.

Exploring the crucial structural elements required for tricyclic quinoline analogs as protein kinase CK2 inhibitors by a combined computational analysis

Protein kinase casein kinase 2 (CK2) is involved in a variety of important cellular physiological processes, and aberrant CK2 activity is associated with a wide variety of human diseases. 5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945) represents the first orally bioavailable and highly selective small molecule inhibitor of CK2. In the present work, a series of tricyclic quinolone analogs were studied by utilizing a combination of three-dimensional quantitative structure activity relationship, molecular docking, and molecular dynamics (MD) simulation methods. CoMFA and CoMSIA analyses were done using ligand-based and receptor-based (RB) alignment schemes, and the RB CoMSIA model (q 2 = 0.647, r 2 = 0.934, r pred 2 = 0.74) including the steric, electronic, and hydrogen bond donor fields shows good correlative and predictive ability. By combining the contour maps of RB CoMSIA model with the binding pocket of human CK2α, the crucial structural elements responsible for inhibitory activity are investigated. Also, the mechanism of how different isomers influence the binding affinity is elucidated from the MD simulation. All these results are in good accordance and complementary to each other, and may provide the rational clues to design more potent CK2 inhibitors.

Studies on the Toxicity of Aromatic Hydrocarbons on Chorella Vulgaris by 3D-QSAR Using CoMFA and CoMSIA Methods

By using CoMFA and CoMSIA methods, the new quantitative structures of 25 aromatic hydrocarbons and the 96 hr-EC50 data with C. vulgaris have been investigated to obtain more detailed insight into the relationships between molecular structure and bioactivity. Compared to CoMFA (the average Q2LOO option =0.610), CoMSIA (the average Q2LOO =0.736) has the better results with robustness and stability. CoMSIA analysis using steric, electrostatic, hydrophobic, and H-bond donor and acceptor descriptors show H-bond donor is the common factor for influencing the toxicity, the steric and electrostatic descriptors are next and the hydrophobic descriptor was last. From the contour maps, the number of benzene ring is more crucial for the compound toxicity and the compounds with more benzene ring make toxicity increased. Under the same number of benzene ring, the kind of substituent group and the formed ability of H-bond are the other parameters to influencing the aromatic hydrocarbons toxicity.

1-(2-Mercaptobenzenesulfonyl)-3-hydroxyguanidines – Novel potent antiproliferatives, synthesis and in vitro biological activity

Twenty four 1-[2-alkylthio-5-(azol-2 or 5-yl)-4-chlorobenzenesulfonyl]-3-hydroxyguanidines 6a–x have been synthesized in order to evaluate their biological activity. Compounds 6a, 6c, 6d, 6f, 6g, 6i–p, 6r–t, and 6v–x were tested for their in vitro anticancer activity at the US National Cancer Institute. The highest in vitro anticancer activity was found for compounds 6d, 6g and 6k with GI50 average value in the range 1.62–1.86 μM, and TGI mean values 3.72–4.47 μM, whereas the remaining compounds showed broad spectrum of anticancer activity at low micromolar GI50 level against all tested cancer cell lines. These results were subjected to CoMSIA analysis to establish quantitative structure–activity relationships. The results evidence that potency of these compounds correlates mainly with hydrophobic and polar surface properties of substituents located both at 2 and 5 positions of 1-(4-chlorobenzenesulfonyl) moiety of investigated 3-hydroxyguanidine series.

3D‐QSAR and Molecular Docking Studies on 3‐Anilino‐4‐Arylmaleimide Derivatives as Glycogen Synthase Kinase‐3β Inhibitors

Glycogen synthase kinase-3, a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders, and Alzheimer's disease. It is important to inhibit glycogen synthase kinase-3 selectively, and the net effect of the glycogen synthase kinase-3 inhibitors thus should be target specific, over other phylogenetically related kinases such as CDK-2. In the present work, we have carried out three-dimensional quantitative structure-activity relationship studies on novel class of 3-anilino-4-arylmaleimide derivatives to have improved cellular activity. Docked conformation of the most active molecule in the series, which shows desirable interactions in the receptor, was taken as template for the alignment of the molecules. Statistically significant CoMSIA (r2(cv)=0.614, r2(ncv)=0.948) and comparative molecular field analysis (r2(cv) =0.652, r2(ncv)=0.958) models were generated using 57 molecules in training set. The predictive ability of CoMSIA and comparative molecular field analysis models was determined using a test set of 17 molecules, which gave predictive correlation coefficients (r2(pred)) of 0.87 and 0.82, respectively, indicating good predictive power. Based on the information derived from CoMSIA and comparative molecular field analysis contour maps, we have identified some key features that explain the observed variance in the activity and have been used to design new anilinoarylmaleimide derivatives. The designed molecules showed better binding affinity in terms of estimated docking scores with respect to the already reported systems, hence suggesting that newly designed molecules can be more potent and selective toward glycogen synthase kinase-3β inhibition.

Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships

The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G2/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.

Insights into the Structural Requirements of PKCβII Inhibitors Based on HQSAR and CoMSIA Analyses

Diabetic cardiomyopathy is a clinical condition diagnosed when ventricular dysfunction develops in patients with diabetes devoid of coronary atherosclerosis and hypertension. The selective inhibition of PKCβII represents an effective approach for treating microvascular complications. HQSAR and CoMSIA studies were performed on a data set of 43 maleimide-based molecules acting as potent inhibitors of PKCβII. HQSAR model yielded an of 0.98 and a cross-validated of 0.85, while CoMSIA modeling of these same data generated an of 0.98 and a cross-validated of 0.85. Both the models show good predictive power having for HQSAR and CoMSIA as 0.63 and 0.75, respectively, indicating the reliability of models. The analysis shows that the terminal substitution with electronegative atom at indole or azaindole ring is essential for PKCβII inhibition, while substitution of bulkier group in linker connecting two heteroaryl rings diminishes the activity. This study is presumably helpful in designing new potent molecules as PKCβII inhibitors in fighting against various diseases related to PKCβII.

Docking and 3D-QSAR (quantitative structure activity relationship) studies of flavones, the potent inhibitors of p-glycoprotein targeting the nucleotide binding domain

In order to explore the interactions between flavones and P-gp, in silico methodologies such as docking and 3D-QSAR were performed. CoMFA and CoMSIA analyses were done using ligand based and receptor guided alignment schemes. Validation statistics include leave-one-out cross-validated R 2 ( q 2), internal prediction parameter by progressive scrambling ( Q ∗2), external prediction with test set. They show that models derived from this study are quite robust. Ligand based CoMFA ( q 2 = 0.747, Q ∗2 = 0.639, r pred 2 = 0.802 ) and CoMSIA model ( q 2 = 0.810, Q ∗2 = 0.676, r pred 2 = 0.785 ) were developed using atom by atom matching. Receptor guided CoMFA ( q 2 = 0.712, Q ∗2 = 0.497, r pred 2 = 0.841 ) and for CoMSIA ( q 2 = 0.805, Q ∗2 = 0.589, r pred 2 = 0.937 ) models were developed by docking of highly active flavone into the proposed NBD (nucleotide binding domain) of P-gp. The 3D-QSAR models generated here predicted that hydrophobic and steric parameters are important for activity toward P-gp. Our studies indicate the important amino acid in NBD crucial for binding in accordance with the previous results. This site forms a hydrophobic site. Since flavonoids have potential without toxicity, we propose to inspect this hydrophobic site including Asn1043 and Asp1049 should be considered for future inhibitor design.

Design, Synthesis, Biological Evaluation, and Structure–Activity Relationships of Substituted Phenyl 4-(2-Oxoimidazolidin-1-yl)benzenesulfonates as New Tubulin Inhibitors Mimicking Combretastatin A-4

Sixty-one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) and 13 of their tetrahydro-2-oxopyrimidin-1(2H)-yl analogues (PPB-SOs) were prepared and biologically evaluated. The antiproliferative activities of PIB-SOs on 16 cancer cell lines are in the nanomolar range and unaffected in cancer cells resistant to colchicine, paclitaxel, and vinblastine or overexpressing the P-glycoprotein. None of the PPB-SOs exhibit significant antiproliferative activity. PIB-SOs block the cell cycle progression in the G2/M phase and bind to the colchicine-binding site on β-tubulin leading to cytoskeleton disruption and cell death. Chick chorioallantoic membrane tumor assays show that compounds 36, 44, and 45 efficiently block angiogenesis and tumor growth at least at similar levels as combretastatin A-4 (CA-4) and exhibit low to very low toxicity on the chick embryos. PIB-SOs were subjected to CoMFA and CoMSIA analyses to establish quantitative structure–activity relationships.

CoMFA and CoMSIA Analyses of Highly Selective Pipecolic Acid Based TNF-α Converting Enzyme (TACE) Inhibitors Using Docked Conformations for Molecular Alignment

CoMFA and CoMSIA Analyses of Highly Selective Pipecolic Acid Based TNF-α Converting Enzyme (TACE) Inhibitors Using Docked Conformations for Molecular Alignment

3D-QSAR and Docking Studies on Pyrrolopyrimidine Derivatives as LIM-Kinase 2 Inhibitors

The pyrrolopyrimidine derivatives have been regarded as a novel class of LIM-kinase 2 inhibitor. To explore the relationship between the structures of substituted pyrrolopyrimidine derivatives and their inhibitory activities against LIMK2, CoMFA and CoMSIA analyses, and molecular docking studies were performed on a dataset of forty-one compounds. The two 3D-QSAR models resulted from thirty-one molecules in the training set gave r2 cv values of 0.635 and 0.660, r2 values of 0.973 and 0.965, respectively. The predictive ability of CoMFA and CoMSIA, determined using a test set of ten compounds, gave predictive correlation coefficients of 0.971 and 0.964, respectively. 3D contour maps generated from CoMFA and CoMSIA along with the docking binding structures provided enough information about the structural requirements for better activity. The results can serve as a useful guideline to design novel LIMK2 inhibitors with better potencies. Keywords: LIMK2, CoMFA, CoMSIA, Docking, Glaucoma

Ligand Based CoMFA, CoMSIA and HQSAR Analysis of CCR5 Antagonists

In this study, we have developed QSAR models for a series of 38 piperidine-4-carboxamide CCR5 antagonists using CoMFA, CoMSIA and HQSAR methods. Developed models showed good statistics in terms of <TEX>$q^2$</TEX> and <TEX>$r^2$</TEX> values. Best predictions obtained with standard CoMFA model (<TEX>$r^2$</TEX> = 0.888, <TEX>$q^2$</TEX> = 0.651) and combined CoMSIA model (<TEX>$r^2$</TEX> = 0.892, <TEX>$q^2$</TEX> = 0.665) with electrostatics and H-bond acceptor parameter. The validity of developed models was assessed by test set of 9 compounds, which showed good predictive correlation coefficient for CoMFA (0.804) and CoMSIA (0.844). Bootstrapped analysis showed statistically significant and robust CoMFA (0.968) and CoMSIA (0.936) models. Best HQSAR model was obtained with a <TEX>$q^2$</TEX> of 0.662 and <TEX>$r^2$</TEX> of 0.936 using atom, connection, hydrogen, donor and acceptor as parameters and fragment size (7-10) with optimum number of 6 components. Predictive power of developed HQSAR model was proved by test set and it was found to be 0.728.

2D and 3D QSAR analyses to predict favorable substitution sites in anilino-monoindolylmaleimides acting as PKCβII selective inhibitors

Diabetic cardiomyopathy (DCM) is a clinical condition, diagnosed when ventricular dysfunction develops in diabetic patients without coronary atherosclerosis and hypertension. Intensive studies on pathogenesis of DCM show PKCβII as one of the mediators, responsible for developing DCM. 2D-QSAR (HQSAR) and 3D-QSAR (CoMSIA) studies were performed on a dataset of 42 anilino-monoindolylmaleimides acting as PKCβII selective inhibitors. Among the different alignment strategies used for CoMSIA study FlexS was found to be the best alignment method. Conformational search was performed for a few molecules to obtain the best model. CoMSIA analysis gave information about sites of favorable substitutions and steered us to assume that alkyl amine substitution on the pharmacophore would be a favorable substituent for improving the biological activity. From HQSAR studies we could extrapolate the presence of tertiary acceptor group may probably be responsible for increase in the activity whereas occurrence of cyclic ring structures would lead to decrease in the activity.

Anthranilate derivatives as TACE inhibitors: Docking based CoMFA and CoMSIA analyses

Anthranilic acid based derivatives (ANTs) have been identified as a novel class of potent tumor necrosis factor-α converting enzyme (TACE) inhibitors. A computational strategy based on molecular docking studies, followed by CoMFA and CoMSIA analyses has been performed to elucidate the atomic details of the TACE/ANT interactions and also to identify the most important features impacting TACE inhibitory activity of ANTs. The CoMSIA model resulted to be slightly more predictive than CoMFA model, and gave conventional r² 0.991, r²(cv) 0.793, q² 0.777, SEE 0.050, F-value 655.610, and r²(test) 0.871. The 3D-QSAR field contributions and the structural features of the TACE binding site showed a good correlation. These studies will be useful to design new TACE inhibitors with improved potency.

Development of predictive pharmacophore model for in silico screening, and 3D QSAR CoMFA and CoMSIA studies for lead optimization, for designing of potent tumor necrosis factor alpha converting enzyme inhibitors

A chemical feature-based pharmacophore model was developed for Tumor Necrosis Factor-alpha converting enzyme (TACE) inhibitors. A five point pharmacophore model having two hydrogen bond acceptors (A), one hydrogen bond donor (D) and two aromatic rings (R) with discrete geometries as pharmacophoric features was developed. The pharmacophore model so generated was then utilized for in silico screening of a database. The pharmacophore model so developed was validated by using four compounds having proven TACE inhibitory activity which were grafted into the database. These compounds mapped well onto the five listed pharmacophoric features. This validated pharmacophore model was also used for alignment of molecules in CoMFA and CoMSIA analysis. The contour maps of the CoMFA/CoMSIA models were utilized to provide structural insight for activity improvement of potential novel TACE inhibitors. The pharmacophore model so developed could be used for in silico screening of any commercial/in house database for identification of TACE inhibiting lead compounds, and the leads so identified could be optimized using the developed CoMSIA model. The present work highlights the tremendous potential of the two mutually complementary ligand-based drug designing techniques (i.e. pharmacophore mapping and 3D-QSAR analysis) using TACE inhibitors as prototype biologically active molecules.