Correlation between nuclear action of anthracycline anticancer agents and their binding affinity to the proteasome

Objective: P53 protein is well known for its role in cell cycle regulation and induction of apoptosis. This protein is degraded by MDM2 mediated proteolysis. Inhibition of interaction between p53 and MDM2 has been recognized as a most potential and selective target for development of novel anticancer agents. Recently, several molecules entered in the clinical trial study for the treatment of various types of cancers are based on inhibition of interaction between p53-MDM2. Therefore, in this study, a novel dihydropyridine based molecules were designed as p53-MDM2 inhibitor, and their anticancer activity (including reference) was determined in comparison with most active anticancer agent and inactive anticancer agents in National Cancer Institute database using “Cancer IN” server.Methods: In this work, a novel dihydropyrimidinone based lead (L11) on the basis of molecular docking study, predicted IC50, anticancer activity, and toxicity profile were designed. Lead L11 was obtained after sequential isosteric replacement of functional groups for optimization in compound L0.Results: The docking scores of L3-L11 found to be in range of 21-25 close to docking score 25 of SAR405838 and better than nutlin-3a. MDM2 binding affinity values (37-78 Kcal/mol) of all ligands were also found to better than that of nutlin-3a (37 Kcal/mol). Surprisingly, MDM2 binding affinity of L11 (78 Kcal/mol) found to be equal to that of SAR405838 and 2-fold greater than nutlin-3a.Conclusion: These data indicating that L11 as a potential lead from dihydropyrimidinones for inhibition of p53-MDM2 interaction.

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Steroidal glycoalkaloids fromSolanum nigrumtarget cytoskeletal proteins: anin silicoanalysis

PeerJ ◽

10.7717/peerj.6012 ◽

2019 ◽

Vol 7 ◽

pp. e6012 ◽

Cited By ~ 2

Author(s):

Rumana Ahmad

Keyword(s):

Binding Affinity ◽

Anticancer Agents ◽

Principal Component ◽

Cytoskeletal Proteins ◽

Hydroxyl Group ◽

Docking Analysis ◽

Drug Candidates ◽

Division Cell

BackgroundSolanum nigrum(black nightshade;S. nigrum), a member of family Solanaceae, has been endowed with a heterogeneous array of secondary metabolites of which the steroidal glycoalkaloids (SGAs) and steroidal saponins (SS) have vast potential to serve as anticancer agents. Since there has been much controversy regarding safety of use of glycoalkaloids as anticancer agents, this area has remained more or less unexplored. Cytoskeletal proteins like actin play an important role in maintaining cell shape, synchronizing cell division, cell motility, etc. and along with their accessory proteins may also serve as important therapeutic targets for potential anticancer candidates. In the present study, glycoalkaloids and saponins fromS. nigrumwere screened for their interaction and binding affinity to cytoskeletal proteins, using molecular docking.MethodsBioactivity score and Prediction of Activity Spectra for Substances (PASS) analysis were performed using softwares Molinspiration and Osiris Data Explorer respectively, to assess the feasibility of selected phytoconstituents as potential drug candidates. The results were compared with two standard reference drugs doxorubicin hydrochloride (anticancer) and tetracycline (antibiotic). Multivariate data obtained were analyzed using principal component analysis (PCA).ResultsDocking analysis revealed that the binding affinities of the phytoconstituents towards the target cytoskeletal proteins decreased in the order coronin>villin>ezrin>vimentin>gelsolin>thymosin>cofilin. Glycoalkaloid solasonine displayed the greatest binding affinity towards the target proteins followed by alpha-solanine whereas amongst the saponins, nigrumnin-I showed maximum binding affinity. PASS Analysis of the selected phytoconstituents revealed 1 to 3 violations of Lipinski’s parameters indicating the need for modification of their structure-activity relationship (SAR) for improvement of their bioactivity and bioavailability. Glycoalkaloids and saponins all had bioactivity scores between −5.0 and 0.0 with respect to various receptor proteins and target enzymes. Solanidine, solasodine and solamargine had positive values of druglikeness which indicated that these compounds have the potential for development into future anticancer drugs. Toxicity potential evaluation revealed that glycoalkaloids and saponins had no toxicity, tumorigenicity or irritant effect(s). SAR analysis revealed that the number, type and location of sugar or the substitution of hydroxyl group on alkaloid backbone had an effect on the activity and that the presence of α-L-rhamnopyranose sugar at C-2 was critical for a compound to exhibit anticancer activity.ConclusionThe present study revealed some cytoskeletal target(s) forS. nigrumphytoconstituents by docking analysis that have not been previously reported and thus warrant further investigations bothin vitroandin vivo.

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Synthesis, spectroscopic investigation, and DFT study of N,N′-disubstituted ferrocene-based thiourea complexes as potent anticancer agents

Dalton Transactions ◽

10.1039/c7dt04090c ◽

2018 ◽

Vol 47 (6) ◽

pp. 1868-1878 ◽

Cited By ~ 15

Author(s):

Faiza Asghar ◽

Saira Fatima ◽

Sadaf Rana ◽

Amin Badshah ◽

Ian S. Butler ◽

...

Keyword(s):

Dna Binding ◽

Anticancer Activity ◽

Binding Affinity ◽

Anticancer Agents ◽

Spectroscopic Investigation ◽

Dft Study ◽

Redox Potentials ◽

Dna Binding Affinity ◽

Dna Binders ◽

Homo Lumo

The DNA binding affinity of ferrocenyl thioureas (A1–A9) explored by CV and UV ascertain them as noble DNA binders. The complexes also publicized decent antioxidant and anticancer activity. DFT-based HOMO/LUMO energies are comparable with experimentally calculated redox potentials.

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A theoretical insight in interactions of some chemical compounds as mTOR inhibitors

Bulletin of the National Research Centre ◽

10.1186/s42269-021-00525-x ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

David Ebuka Arthur ◽

Jibrin Noah Akoji ◽

Riadh Sahnoun ◽

Greatman C. Okafor ◽

Karimatu Lami Abdullahi ◽

...

Keyword(s):

Hydrogen Bond ◽

Binding Affinity ◽

Anticancer Agents ◽

Mtor Inhibitors ◽

Stable Complex ◽

Hydrogen Bond Energy ◽

Atp Binding Site ◽

Binding Pockets ◽

Theoretical Insight ◽

High Binding Affinity

Abstract Background A series of known Food and Drug Administration (FDA) approved anticancer drugs were collected from the literature and docked against mTOR receptor which has been identified in present time as a target for therapeutic anticancer agents. The compounds binding affinity were calculated after minimising the interaction within the binding pockets’ of the mTOR (4JT6) receptor. Results The result shows that PF-04691502 ligand best inhibited mTOR while occupying the Adenosine triphosphate (ATP)-binding site on the receptor. PF-04691502 had the best binding affinity with a reported value of − 39.261 kcal/mol, and a hydrogen bond energy contribution of − 8.326 kcal/mol. Polamid529 is also found to have a good binding affinity of − 36.75 kcal/mol with the receptor, but was less significant than that calculated for the reference or standard inhibitor (X6K) used (− 37.862 kcal/mol). Further analysis revealed that Palomid529 formed a more stable complex with the receptor than torin2 and X6K due to the significant hydrogen bond contributions it adds to its overall binding score. Conclusion PF-04691502 ligand was identified as the best inhibitor due to its high binding affinity for mTOR and should be considered as the best alternative to the reference inhibitor X6K.

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New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents

International Journal of Molecular Sciences ◽

10.3390/ijms222212272 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12272

Author(s):

Rania Hamdy ◽

Arwyn T. Jones ◽

Mohamed El-Sadek ◽

Alshaimaa M. Hamoda ◽

Sarra B. Shakartalla ◽

...

Keyword(s):

Binding Affinity ◽

Cell Lines ◽

Anticancer Agents ◽

Inhibitory Activity ◽

Human Cancer ◽

Drug Candidate ◽

Human Cancer Cell Lines ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Ic50 Values

A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (5a–l) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (1) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (2), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (3). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (5a–l). The novel series showed selective sub-micromolar IC50 growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (5k) showed selective IC50 values of 0.31–0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (5k) with an IC50 value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate.

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Dimeric and Multimeric DNA Aptamers for Highly Effective Protein Recognition

Molecules ◽

10.3390/molecules25225227 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5227 ◽

Cited By ~ 1

Author(s):

Claudia Riccardi ◽

Ettore Napolitano ◽

Domenica Musumeci ◽

Daniela Montesarchio

Keyword(s):

Binding Affinity ◽

Anticancer Agents ◽

Building Blocks ◽

Protein Recognition ◽

Therapeutic Activity ◽

G Quadruplex ◽

Biological Target ◽

Activity Enhancement ◽

Improved Performance ◽

Target Binding

Multivalent interactions frequently occur in biological systems and typically provide higher binding affinity and selectivity in target recognition than when only monovalent interactions are operative. Thus, taking inspiration by nature, bivalent or multivalent nucleic acid aptamers recognizing a specific biological target have been extensively studied in the last decades. Indeed, oligonucleotide-based aptamers are suitable building blocks for the development of highly efficient multivalent systems since they can be easily modified and assembled exploiting proper connecting linkers of different nature. Thus, substantial research efforts have been put in the construction of dimeric/multimeric versions of effective aptamers with various degrees of success in target binding affinity or therapeutic activity enhancement. The present review summarizes recent advances in the design and development of dimeric and multimeric DNA-based aptamers, including those forming G-quadruplex (G4) structures, recognizing different key proteins in relevant pathological processes. Most of the designed constructs have shown improved performance in terms of binding affinity or therapeutic activity as anti-inflammatory, antiviral, anticoagulant, and anticancer agents and their number is certainly bound to grow in the next future.

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Discovery of a Highly Potent and Novel Gambogic Acid Derivative as an Anticancer Drug Candidate

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200408080040 ◽

2020 ◽

Vol 20 ◽

Author(s):

Huiping Ling ◽

Hong Li ◽

Meijun Chen ◽

Baolong Lai ◽

Haiming Zhou ◽

...

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

Anticancer Agents ◽

Docking Study ◽

Gambogic Acid ◽

Drug Candidate ◽

Molecular Docking Study ◽

Discovery Studio ◽

Mcf 7

Background and Purpose: Gambogic acid (GA), a promising anti-cancer agent isolated from the resin of Garcinia species in Southeast Asia, exhibits high potency in inhibiting a wide variety of cancer cells growth. Moreover, the fact that it is amenable to chemical modification makes GA an attractive molecule for the development of anticancer agents. Methods: Gambogic acid-3-(4-pyrimidinyloxy) propyl ester (compound 4) was derived from the reaction between 4-hydroxypropoxy pyrimidine and GA. Its structure was elucidated by comprehensive analysis of ESIMS, HRESIMS, 1 D NMR data. Antitumor activities of compound 4 and GA in vitro against HepG-2, A549 and MCF-7 cells were investigated by MTT assay. FITC/PI dye were used to test apoptosis. The binding affinity difference of compound 4 and GA binding to IKKβ was studied by using Discovery Studio 2016. Results: Compound 4 was successfully synthesized and showed strong inhibitory effects on HepG-2, A549 and MCF-7 cells lines with IC50 value of 1.49 ± 0.11, 1.37 ± 0.06 and 0.64 ± 0.16μM, respectively. Molecular docking study demonstrated that four more hydrogen bonds were established between IKKβ and compound 4, compared with GA. Conclusion: Our results suggested that compound 4 showed significant effects in inducing apoptosis. Further molecular docking study indicated that the introduction of pyrimidine could improve GA’s binding affinity to IKKβ. Compound 4 may serve as a potential lead compound for the development of new anticancer drugs.

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Virtual Screening of Novel Hybrid Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): Exploring Multiple Targeted Cancer Therapy by an In Silico Approach

Current Cancer Therapy Reviews ◽

10.2174/1573394715666190618114748 ◽

2020 ◽

Vol 16 (1) ◽

pp. 70-77

Author(s):

Ashish P. Shah ◽

Chhagan N. Patel

Keyword(s):

Cancer Therapy ◽

Virtual Screening ◽

Binding Affinity ◽

Anticancer Agents ◽

In Silico ◽

Software Tool ◽

Docking Studies ◽

Targeted Cancer Therapy ◽

Bioactivity Prediction ◽

Glide Docking

Background: Dual-targeting/Multi-targeting of oncoproteins by a single drug molecule represents an efficient, logical and alternative approach to drug combinations. In silico methods are useful tool for the search and design of selective multi-target agents. Objective: The objective of the present study was to design new hybrid compounds by linking the main structural unit of the NSAIDs with the benzothiazole and thiadiazole ring and to discover new hybrid NSAIDs as multi targeted anticancer agents through in silico approach. Method: Structure-based virtual screening was performed by applying ADMET filtration and Glide docking using Virtual screening Workflow. The docking studies were performed on three different types of receptors TNF-α, COX-II and protein kinase. Bioactivity prediction of screened compounds were done using Molinspiration online software tool. Results: Out of 54 designed compounds eighteen were screened on the basis of binding affinity on various receptors and ADMET filtration. Bioactivity prediction reveals that screened compounds may act through kinase inhibition or enzyme inhibition. Compounds 2sa, 5sa, 6sa and 7sa shows higher binding affinity with all three receptors. Conclusion: The study concluded that compound 2sa, 5sa, 6sa, and 7sa could be further explored for multiple targeted cancer therapy.

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