Molecular docking analysis of HER-2 inhibitor from the ZINC database as anticancer agents.
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ABSTRACT:
SUBMITTER: Sait KHW
PROVIDER: S-EPMC8573456 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The pyruvate kinase M2 isoform (PKM2) is linked with cancer. Therefore, it is of interest to document the molecular docking analysis of Pyruvate Kinase M2 (PDB ID: 4G1N) with potential activators from the ZINC database. Thus, we document the optimal molecular docking features of a compound having ID ZINC000034285235 with PKM2 for further consideration.
| S-EPMC8340708 | biostudies-literature
Project description:ObjectiveCinnamaldehyde (CM) has a molecular structure with the main reaction center of an aromatic ring which the bioactivity can be modified as an anticancer agent by substituting the groups in the ortho (o), meta (m), and para (p) position. The present study aimed to investigate the correlation of the cluster region that was substituted in CM on its activity for various anticancer receptors.MethodsThe receptor types used in the test were 5FL6, 1HOV, 4GY7, 5EAM, 4XCU, 4EL9, and 4PQW. The suitability of the hydroxy (OH) and methoxy (OMe) groups, which were substituted, was studied based on the value of Ki, their interactions with metal cofactors, and the type of amino acid residues that function as cancer receptor inhibitors. The docking was conducted using AutoDock 4.ResultsThe study results showed that all derivative compounds (o, m, and p) -OH and -OMe CM commonly had better anticancer activities than CM. o-OH CM has the best activity against receptors 5FL6, 1HOV, 4GY7, 5EAM, and 4XCU, and m-OMe CM has better activity against the 4EL9 receptors when compared with other CM derivatives.ConclusionBased on this study, the compound derived from CM, i.e. OHC, tends to show the best anticancer activity..
| S-EPMC8629477 | biostudies-literature
Project description:The enzyme, α-topoisomerase II (α-Topo II), is known to regulate efficiently the topology of DNA. It is highly expressed in rapidly proliferating cells and plays an important role in replication, transcription and chromosome organisation. This has prompted several investigators to pursue α-Topo II inhibitors as anticancer agents. δ-Carboline, a natural product, and its synthetic derivatives are known to exert potent anticancer activity by selectively targeting α-Topo II. Therefore, it is of interest to design carboline derivatives fused with pyrrolidine-2,5-dione in this context. δ-Carbolines fused with pyrrolidine-2,5-dione are of interest because the succinimide part of fused heteroaromatic molecule can interact with the ATP binding pocket via the hydrogen bond network with selectivity towards α-Topo II. The 300 derivatives designed were subjected to the Lipinski rule of 5, ADMET and toxicity prediction. The designed compounds were further analysed using molecular docking analysis on the active sites of the α-Topo II crystal structure (PDB ID:1ZXM). Molecular dynamic simulations were also performed to compare the binding mode and stability of the protein-ligand complexes. Compounds with ID numbers AS89, AS104, AS119, AS209, AS239, AS269, and AS299 show good binding activity compared to the co-crystal ligand. Molecular Dynamics simulation studies show that the ligand binding to α-Topo II in the ATP domain is stableand the protein-ligand conformation remains unchanged. Binding free energy calculations suggest that seven molecules designed are potential inhibitors for α-Topo II for further consideration as anticancer agents.
| S-EPMC8340707 | biostudies-literature
Project description:Glycyrrhizin (GA) analogs in the form of 3-glucuronides and 18-epimers were synthesized and their anticancer activities were evaluated. Alkaline isomerization of monoglucuronides is reported. In vitro and in vivo studies showed that glycyrrhetinic acid monoglucuronides (GAMGs) displayed higher anticancer activities than those of bisglucuronide GA analogs, while anticancer activity of the 18?-epimer was superior to that of the 18?-epimer. 18?-GAMG was firstly nicely bound to epidermal growth factor receptor (EGFR) via six hydrogen bonds and one charge interaction, and the docking calculation proved the correlation between anticancer activities and EGFR inhibitory activities. Highly active 18?-GAMG is thus of interest for the further studies as a potential anticancer agent.
| S-EPMC6271220 | biostudies-literature
Project description:In the present paper, new pyrimidine derivatives were designed, synthesized and analyzed in terms of their anticancer properties. The tested compounds were evaluated in vitro for their antitumor activity. The cytotoxic effect on normal human dermal fibroblasts (NHDF) was also determined. According to the results, all the tested compounds exhibited inhibitory activity on the proliferation of all lines of cancer cells (colon adenocarcinoma (LoVo), resistant colon adenocarcinoma (LoVo/DX), breast cancer (MCF-7), lung cancer (A549), cervical cancer (HeLa), human leukemic lymphoblasts (CCRF-CEM) and human monocytic (THP-1)). In particular, their feature stronger influence on the activity of P-glycoprotein of cell cultures resistant to doxorubicin than doxorubicin. Tested compounds have more lipophilic character than doxorubicin, which determines their affinity for the molecular target and passive transport through biological membranes. Moreover, the inhibitory potential against topoisomerase II and DNA intercalating properties of synthesized compounds were analyzed via molecular docking.
| S-EPMC8067809 | biostudies-literature
Project description:Pyrazoles, thiazoles and fused thiazoles have been reported to possess many biological activities. 3-Methyl-5-oxo-4-(2-arylhydrazono)-4,5-dihydro-1H-pyrazole-1-carbothioamides 3a,b (obtained from the reaction of ethyl 3-oxo-2-(2-arylhydrazono)butanoates 1a,b with thiosemicarbazide) could be transformed into a variety of thiazolyl-pyrazole derivatives 6a-h, 10a-c, 15a-c, 17, 19 and 21 via their reaction with a diversity hydrazonoyl chlorides as well as bromoacetyl derivatives. Moreover, the computational studies were carried out for all new compounds. The results indicated that five compounds showed promising binding affinities (10a: -?3.4 kcal/mol, 6d: -?3.0 kcal/mol, 15a: -?2.2 kcal/mol, 3a: -?1.6 kcal/mol, and 21: -?1.3 kcal/mol) against the active site of the epidermal growth factor receptor kinase (EGFR). The cytotoxicity of the potent products 3a, 6d, 10a, 15a, and 21 was examined against human liver carcinoma cell line (HepG-2) and revealed activities close to Doxorubicin standard drug. There was an understanding between the benefits of restricting affinities and the data obtained from the practical anticancer screening of the tested compounds.
| S-EPMC6760062 | biostudies-literature
Project description:The diverse pharmacological role of dihydropyrimidinone scaffold has made it to be an interesting drug target. Because of the high incidence and mortality rate of breast cancer, there is a dire need of discovering new pharmacotherapeutic agents in managing this disease. A series of twenty-two derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a-3k) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a-4k) synthesized in a previous study were evaluated for their anticancer potential against breast cancer cell line. Molecular docking studies were performed to analyze the binding mode and interaction pattern of these compounds against nine breast cancer target proteins. The in vitro cell proliferation assay was performed against the breast cancer cell line MCF-7. The structure activity relationship of these compounds was further studied using QSARINS. Among nine proteins, the docking analysis revealed efficient binding of compounds 4f, 4e, 3e, 4g, and 4h against all target proteins. The in vitro cytotoxic assay revealed significant anticancer activity of compound 4f having IC50 of 2.15 μM. The compounds 4e, 3e, 4g, and 4h also showed anticancer activities with IC50 of 2.401, 2.41, 2.47 and 2.33 μM, respectively. The standard tamoxifen showed IC50 1.88 μM. The 2D qualitative structure-activity relationship (QSAR) analysis was also carried out to identify potential breast cancer targets through QSARINS. The final QSAR equation revealed good predictivity and statistical validation R 2 and Q 2 values for the model obtained from QSARINS was 0.98 and 0.97, respectively. The active compounds showed very good anticancer activities, and the binding analysis has revealed stable hydrogen bonding of these compounds with the target proteins. Moreover, the QSAR analysis has predicted useful information on the structural requirement of these compounds as anticancer agents with the importance of topological and autocorrelated descriptors in effecting the cancer activities.
| S-EPMC9061032 | biostudies-literature
Project description:Dichloroacetate (DCA) is a simple and small anticancer drug that arouses the activity of the enzyme pyruvate dehydrogenase (PDH) through inhibition of the enzyme pyruvate dehydrogenase kinases (PDK1-4). DCA can selectively promote mitochondria-regulated apoptosis, depolarizing the hyperpolarized inner mitochondrial membrane potential to normal levels, inhibit tumor growth and reduce proliferation by shifting the glucose metabolism in cancer cells from anaerobic to aerobic glycolysis. In this study, a series of DCA analogues were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis-based multiple linear regression (FA-MLR), principal component regression (PCR), and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were applied to make relations between structural characteristics and cytotoxic activities of a variety of DCA analogues. The best multiple linear regression equation was obtained from genetic algorithms partial least squares, which predict 90% of variances. Based on the resulted model, an in silico-screening study was also conducted and new potent lead compounds based on new structural patterns were designed. Molecular docking as well as protein ligand interaction fingerprints (PLIF) studies of these compounds were also investigated and encouraging results were acquired. There was a good correlation between QSAR and docking results.
| S-EPMC5610753 | biostudies-literature
Project description:BackgroundThe amide derivatives of nonsteroidal anti-inflammatory drugs have been reported to possess antitumor activity. The present work describes the synthesis of dexibuprofen amide analogues (4a-j) as potential anticancer agents.MethodsThe title amides (4a-j) were obtained by simple nucleophilic substitution reaction of dexibuprofen acid chloride with substituted amines in good yield and chemical structures were confirmed by FTIR, 1H NMR, 13C NMR and mass spectral data.ResultsThe brine shrimp lethality assay results showed that all of the synthesized compounds are non-toxic to shrimp larvae. The inhibitory effects on tumor growth were evaluated and it was observed that N-(2,5-dichlorophenyl)-2-(4-isobutylphenyl) propionamide (4e) and N-(2-chlorophenyl)-2-(4-isobutylphenyl) propionamide (4g) exhibited excellent antitumor activity compared to all other derivatives. The compound 4e bearing 2,5-dichloro substituted phenyl ring and 4g possesses 2-chloro substituted phenyl ring exhibited 100% inhibition of the tumor growth. The anticancer activity was evaluated against breast carcinoma cell line (MCF-7) and it was observed that derivative 4e exhibited excellent growth inhibition of cancer cells with IC50 value of 0.01±0.002 µm, which is better than the standard drugs. The docking studies against breast cancer type 1 susceptibility protein BRCA1 (PDBID 3K0H) exhibited good binding affinities, which are in good agreement with the wet lab results. The compounds 4e and 4g showed the binding energy values of -6.39 and -6.34 Kcal/mol, respectively. The molecular dynamic (MD) simulation was also carried out to evaluate the residual flexibility of the best docking complexes of compounds 4e and 4g. The MD simulation analysis assured that the 4e formed a more stable complex with the target protein than the 4g. The synthesized amide derivatives exhibited were devoid of gastrointestinal side effects and no cytotoxic effects against human normal epithelial breast cell line (MCF-12A) were found.ConclusionBased upon our wet lab and dry lab findings we propose that dexibuprofen analogue 4e may serve as a lead structure for the design of more potent anticancer drugs.
| S-EPMC6524612 | biostudies-literature
Project description:The search for anticancer metal-based drugs alternative to platinum derivatives could not exclude zinc derivatives due to the importance of this metal for the correct functioning of the human body. Zinc, the second most abundant trace element in the human body, is one of the most important micro-elements essential for human physiology. Its ubiquity in thousands of proteins and enzymes is related to its chemical features, in particular its lack of redox activity and its ability to support different coordination geometries and to promote fast ligands exchange. Analogously to other trace elements, the impairment of its homeostasis can lead to various diseases and in some cases can be also related to cancer development. However, in addition to its physiological role, zinc can have beneficial therapeutic and preventive effects on infectious diseases and, compared to other metal-based drugs, Zn(II) complexes generally exert lower toxicity and offer few side effects. Zinc derivatives have been proposed as antitumor agents and, among the great number of zinc coordination complexes which have been described so far, this review focuses on the design, synthesis and biological studies of zinc complexes comprising N-donor ligands and that have been reported within the last five years.
| S-EPMC7763991 | biostudies-literature