Topochemical models for the prediction of voltage-gated sodium channel binding activity of hydantoins and related non-hydantoins

The relationship of Wiener’s topochemical index—a distance based topochemical index, molecular connectivity topochemical index—an adjacency based topochemical index and eccentric connectivity topochemical index—an adjacency-cum-distance based topochemical index with sodium channel binding activity has been investigated. A dataset comprising 50 hydantoins and related non-hydantoins was selected. The dataset was divided equally into training and test sets. The values of the three topochemical indices for all the compounds present in both the training and test sets were computed using an in-house computer program. The resulting data was analyzed and suitable models were developed after identification of the active ranges in the training set. Subsequently, a biological activity was assigned to each compound involved in the training set using these models, which was then compared with the reported sodium channel binding activity. An accuracy of prediction of the order of >99% was observed using the proposed models. Cross-validation of these models using the test set revealed an exceptionally high accuracy of ∼95%. 3,5-disubstituted-5-phenylhydantoin     

Predicting anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-ones: computational approach using reformed eccentric connectivity index

The eccentric connectivity index, which has recently been employed successfully for the development of numerous mathematical models for the prediction of biological activities of diverse nature, has been reformed to overcome its limitations caused by degeneracy and insensitivity towards heteroatoms. The reformed eccentric connectivity index, termed the eccentric connectivity topochemical index, overcomes the limitations of the eccentric connectivity index by exhibiting very low degeneracy and displaying sensitivity to both the presence and relative position of heteroatoms without compromizing the discriminating power of the eccentric connectivity index. The relationship of the eccentric connectivity topochemical index, eccentric connectivity index and Wieners index with regard to the anti-HIV activity of 2, 3-diaryl-1, 3-thiazolidin-4-one derivatives was subsequently investigated. The values of the eccentric connectivity topochemical index, the eccentric connectivity index and Wieners index of each of 31 analogues comprizing the data set were computed using in-house computer program. Resultant data was analyzed and suitable models developed after identification of active ranges. Subsequently, each derivative was assigned a biological activity using these models, which was then compared with the reported anti-HIV activity. The accuracy of prediction using these models was found to vary from 81 to 90%. The proposed index offers a vast potential for virtual screening of combinatorial libraries, structure property/activity studies and drug design.Figure Basic structure of 2,3-diaryl-1, 3-thiazoidin-4-ones.     

Topological models for the prediction of anti-HIV activity of dihydro (alkylthio) (naphthylmethyl) oxopyrimidines

Relationship between the topological indices and anti-HIV activity of Dihydro (alkylthio) (naphthylmethyl) oxopyrimidines has been investigated. Three topological indices--the Wiener's index--a distance-based topological index, molecular connectivity index--an adjacency based topological index and eccentric connectivity index--an adjacency-cum-distance based topological index were used for the present investigations. A data set comprising of 67 analogues of dihydro (alkylthio) (naphthylmethyl) oxopyrimidine (S-DABO) was selected for the present investigations. The values of the Wiener's index, molecular connectivity index and eccentric connectivity index for each of the 67 compounds comprising the data set were computed using an in house computer program. Resultant data were subsequently analyzed and suitable models were developed after identification of active ranges. Subsequently, a biological activity was assigned to each compound using these models, which was then compared with the reported anti-HIV activity. The use of models based upon these topological indices resulted in prediction of anti-HIV activity with an accuracy ranging from 86% to 89%.     

Molecular-docking-guided 3D-QSAR studies of substituted isoquinoline-1,3-(2H,4H)-diones as cyclin-dependent kinase 4 (CDK4) inhibitors

The cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression, and are involved in uncontrolled cell proliferation—a hallmark of cancer. This suggests that small molecular inhibitors of CDKs might be attractive as prospective antitumor agents. To explore the relationship between the structures of substituted isoquinoline-1,3-(2H,4H)-diones and their inhibition of CDK4, 3D-QSAR studies were performed on a dataset of 48 compounds. The bioactive conformation of template compound 34 was obtained by performing molecular docking into the ATP binding site of the homology model of CDK4 and ranking by highest consensus score, which was then used to build and align the rest of the molecules in the series. The constructed comparative molecular similarity indices analysis (CoMSIA) produces significantly better results than comparative molecular field analysis (CoMFA), with r_\textcv² r_{\text{cv}}^2 = 0.707 and r ² = 0.988. The contours analysis provides useful information about the structural requirements for substituted isoquinoline-1,3-(2H,4H)-diones for CDK4 inhibitory activity.     

New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis,CDK2 inhibition,QSAR and molecular docking studies

Motivated by the potential anticancer activity of both coumarin and 2-aminothiazole nuclei, a new set of thiazol-2-yl hydrazono-chromen-2-one analogs were efficiently synthesized aiming to obtain novel hybrids with potential cytotoxic activity. MTT assay investigated the significant potency of all the target compounds against the human cervical cancer cell lines (HeLa cells). Cell cycle analysis showed that the representative compound 8a led to cell cycle cessation at G0/G1 phase indicating that CDK2/E1complex could be the plausible biological target for these newly synthesized compounds. Thus, the most active compounds (7c and 8a-c) were tested for their CDK2 inhibitory activity. The biological results revealed their significant CDK2 inhibitory activity with IC₅₀ range of 0.022–1.629 nM. Moreover, RT-PCR gene expression assay showed that compound 8a increased the levels of the nuclear CDK2 regulators P21 and P27 by 2.30 and 5.7 folds, respectively. ELISA tequnique showed also that compound 8a led to remarkable activation of caspases-9 and -3 inducing cell apoptosis. QSAR study showed that the charge distribution and molecular hydrophobicity are the structural features affecting cytotoxic activity in this series. Molecular docking study for the most potent cytotoxic compounds (7c and 8a-c) rationalized their superior CDK2 inhibitory activity through their hydrogen bonding and hydrophobic interactions with the key amino acids in the CDK2 binding site. Pharmacokinetic properties prediction of the most potent compounds showed that the newly synthesized compounds are not only with promising antitumor activity but also possess promising pharmacokinetic properties.     

Development of newly synthesised quinazolinone-based CDK2 inhibitors with potent efficacy against melanoma

Inhibiting Cyclin-dependent kinase 2 (CDK2) has been established as a therapeutic strategy for the treatment of many cancers. Accordingly, this study aimed at developing a new set of quinazolinone-based derivatives as CDK2 inhibitors. The new compounds were evaluated for their anticancer activity against sixty tumour cell lines. Compounds 5c and 8a showed excellent growth inhibition against the melanoma cell line MDA-MB-435 with GI% of 94.53 and 94.15, respectively. Cell cycle analysis showed that compound 5c led to cell cycle cessation at S phase and G2/M phase revealing that CDK2 could be the plausible biological target. Thus, the most cytotoxic candidates 5c and 8a were evaluated in vitro for their CDK2 inhibitory activity and were able to display significant inhibitory action. The molecular docking study confirmed the obtained results. ADME study predicted that 5c had appropriate drug-likeness properties. These findings highlight a rationale for further development and optimisation of novel CDK2 inhibitors.     

Novel 2H-isoquinolin-3-ones as antiplasmodial falcipain-2 inhibitors

A series of 1-aryl-6,7-disubstituted-2H-isoquinolin-3-ones (2–10) was synthesized and evaluated for their inhibition against Plasmodium falciparum cysteine protease falcipain-2, as well as against cultured P. falciparum strain FCBR parasites. All compounds displayed inhibitory activity against recombinant falcipain-2 and against in vitro cultured intraerythrocytic P. falciparum, with the exception of 9. The new compounds exhibited no selectivity against human cysteine proteases such as cathepsins B and L. The inhibitory activity of the synthesized compounds was also evaluated against another protozoal cysteine protease, namely rhodesain of Trypanosoma brucei rhodesiense.     

Regulatory phosphorylation of cyclin-dependent kinase 2: insights from molecular dynamics simulations

The structures of fully active cyclin-dependent kinase-2 (CDK2) complexed with ATP and peptide substrate, CDK2 after the catalytic reaction, and CDK2 inhibited by phosphorylation at Thr14/Tyr15 were studied using molecular dynamics (MD) simulations. The structural details of the CDK2 catalytic site and CDK2 substrate binding box were described. Comparison of MD simulations of inhibited complexes of CDK2 was used to help understand the role of inhibitory phosphorylation at Thr14/Tyr15. Phosphorylation at Thr14/Tyr15 causes ATP misalignment for the phosphate-group transfer, changes in the Mg²⁺ coordination sphere, and changes in the H-bond network formed by CDK2 catalytic residues (Asp127, Lys129, Asn132). The inhibitory phosphorylation causes the G-loop to shift from the ATP binding site, which leads to opening of the CDK2 substrate binding box, thus probably weakening substrate binding. All these effects explain the decrease in kinase activity observed after inhibitory phosphorylation at Thr14/Tyr15 in the G-loop. Interaction of the peptide substrate, and the phosphorylated peptide product, with CDK2 was also studied and compared. These results broaden hypotheses drawn from our previous MD studies as to why a basic residue (Arg/Lys) is preferred at the P₊₂ substrate position. Figure View of the substrate binding site of the fully active cyclin-dependent kinase-2 (CDK2) (pT160-CDK2/cyclin A/ATP). The pThr160 activation site is located in the T-loop (yellow secondary structure). The G-loop, which partly forms the ATP binding site, is shown in blue. The Thr14 and Tyr15 inhibitory phosphorylation sites located in the G-loop are shown in licorice representation     

Comparative sensitivity of liver monoamine oxidases of frog and whitefish to some tricyclic compounds

There is performed a comparative analysis of action of four acridine derivatives and of one xanthene derivative (pyronin G) on activity of liver monoamine oxidase (MAO) of two species of poikilothermal freshwater animals: a representative of amphibians—the common frog Rana temporaria and a representative of the Salmonidae order—the European whitefish Coregonus lavaretus. The studied synthetic hexamember tricyclic compounds show the irreversible character of inhibition of intermediate potency towards the enzyme from the both biological sources. There are obtained qualitative and quantitative differences in the reaction ability and selectivity of action of the studied inhibitors for liver MAO of frog and whitefish. The obtained data of the inhibitory analysis with use of specific substrates are an indirect proof for the existence in liver of the studies frog species of two molecular forms, whereas in the whitefish liver—the single molecular MAO form.     

Topological models for prediction of anti-inflammatory activity of N-arylanthranilic acids

Relationship of anti-inflammatory activity of N-arylanthranilic acids with distance based Wiener's index, adjacency based Zagreb indices M1 and M2, and distance-cum-adjacency based eccentric connectivity index (ECI) was investigated. A dataset comprising of 112 N-arylanthranilic acids was selected. The values of all the four indices for each of the 112 compounds were calculated using an in-house computer program. The dataset was divided randomly into training and test sets. The data was analyzed and suitable models were developed after identification the active ranges in the training set. Subsequently, a biological activity was assigned to each of the compound involved in the test set using these models, which was then compared with the reported anti-inflammatory activity. High accuracy of prediction ranging from 83% to 90% was observed using models based upon topological indices.