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Molecular designing and in silico evaluation of darunavir derivatives as anticancer agents.

ABSTRACT: Darunavir is a synthetic nonpeptidic protease inhibitor which has been tested for anticancer properties. To deduce and enhance the anticancer activity of the Darunavir, we have modified its reactive moiety in an effective way. We designed 9 analogues in ChemBioOffice 2010 and minimized using the LigPrep tool of Schrödinger 2011. These analogues can obstruct the activity of other signalling pathways which are implicated in many tumors. Results of the QikProp showed that all the analogues lied in the specified range of all the pharmacokinetic (ADMET) properties required to become the successful drug. Docking study was performed to test its anticancer activity against the biomarkers of the five main types of cancers i.e. bone, brain, breast, colon and skin cancer. Grid was generated for each oncoproteins by specifying the active site amino acids. The binding model of best scoring analogue with each protein was assessed from their G-scores and disclosed by docking analysis using the XP visualizer tool. An analysis of the receptor-ligand interaction studies revealed that these nine Darunavir analogues are active against all cancer biomarkers and have the features to prove themselves as anticancer drugs, further to be synthesized and tested against the cell lines.

SUBMITTER: Mahto MK

PROVIDER: S-EPMC4070053 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Molecular designing and in silico evaluation of darunavir derivatives as anticancer agents.

Mahto Manoj Kumar MK Yellapu Nanda Kumar NK Kilaru Ravendra Babu RB Chamarthi Naga Raju NR Bhaskar Matcha M

Bioinformation 20140423 4

Darunavir is a synthetic nonpeptidic protease inhibitor which has been tested for anticancer properties. To deduce and enhance the anticancer activity of the Darunavir, we have modified its reactive moiety in an effective way. We designed 9 analogues in ChemBioOffice 2010 and minimized using the LigPrep tool of Schrödinger 2011. These analogues can obstruct the activity of other signalling pathways which are implicated in many tumors. Results of the QikProp showed that all the analogues lied in ...[more]

PMID: 24966524

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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.

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.

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Molecular designing and in silico evaluation of darunavir derivatives as anticancer agents.

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Molecular designing and in silico evaluation of darunavir derivatives as anticancer agents.

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