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Comparative molecular docking and molecular-dynamic simulation of wild-type- and mutant carboxylesterase with BTA-hydrolase for enhanced binding to plastic.

ABSTRACT: According to the literature review, microbial degradation of polyethylene terephthalate by PETases has been detected effective and eco-friendly. However, the number of microorganisms capable of such feats is limited with some undesirable bioprospecting results. BTA-hydrolase has been already reported capable of degrading polyethylene terephthalate. Therefore, mutation by in silico site-directed mutagenesis means to introduce current isomer of PETase for polyethylene terephthalate degradative capability as a better approach to resolve this issue. This study aimed to use in silico site-directed mutagenesis to convert a carboxylesterase from Archaeoglobus fulgidus to BTA-hydrolase from Thermobifida fusca by replacing six amino acids in specific locations. This work was followed by molecular docking analysis with polyethylene terephthalate and polypropylene to compare their interactions. The best-docked enzyme-substrate complex was further subjected to molecular dynamics simulation to gauge the binding quality of the BTA-hydrolase, wild-type and mutant-carboxylesterase with only polyethylene terephthalate as a substrate. Results of molecular docking revealed lowest binding energy for the wild-type carboxylesterase-polypropylene complex (-7.5 kcal/mol). The root-mean-square deviation value was observed stable for BTA-hydrolase. Meanwhile, root-mean-square fluctuation was assessed with higher fluctuation for the mutated residue Lys178. Consequently, the Rg value for BTA-hydrolase-ligand complex (∼1.68 nm) was the lowest compared to the mutant and wild-type carboxylesterase. The collective data conveyed that mutations imparted a minimal change in the ability of the mutant carboxylesterase to bind to polyethylene terephthalate.

SUBMITTER: Lameh F

PROVIDER: S-EPMC8727734 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Comparative molecular docking and molecular-dynamic simulation of wild-type- and mutant carboxylesterase with BTA-hydrolase for enhanced binding to plastic.

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