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Homology modeling and docking studies of ENPP4: a BCG activated tumoricidal macrophage protein.

ABSTRACT: The 3D structure and functions of ENPP4, a protein expressed on the surface of Bacillus Calmette-Guerin (BCG)-activated macrophages, are unknown. In this study, we analyzed the 3D structure of ENPP4 and determined its tumoricidal effects on MCA207 cells.Homology modeling showed that Arg305, Tyr341, Asn291, and Asn295 are important residues in substrate, adenosine triphosphate (ATP), binding. A molecular dynamics study was also carried out to study the stability of ENPP4 (including zinc atoms) as well as its ligand-enzyme complex. BCG increased ENPP4 expression in macrophages, and specific blocking of ENPP4 in BCG-activated macrophages (BAMs) significantly reduced their cytotoxicity against MCA207 cells.These results indicate that zinc remains inside the ENPP4 protein, a BCG activated tumoricidal macrophage protein, throughout the simulation. Important information for the design of new inhibitors was obtained.

SUBMITTER: Yan D

PROVIDER: S-EPMC4730737 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Homology modeling and docking studies of ENPP4: a BCG activated tumoricidal macrophage protein.

Yan Dongmei D Han Weiwei W Dong Zehua Z Liu Qihui Q Jin Zheng Z Chu Dong D Tian Yuan Y Zhang Jinpei J Song Dandan D Wang Dunhuang D Zhu Xun X

Lipids in health and disease 20160128

<h4>Background</h4>The 3D structure and functions of ENPP4, a protein expressed on the surface of Bacillus Calmette-Guerin (BCG)-activated macrophages, are unknown. In this study, we analyzed the 3D structure of ENPP4 and determined its tumoricidal effects on MCA207 cells.<h4>Results</h4>Homology modeling showed that Arg305, Tyr341, Asn291, and Asn295 are important residues in substrate, adenosine triphosphate (ATP), binding. A molecular dynamics study was also carried out to study the stability ...[more]

PMID: 26823374

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Project description:ObjectiveThis work was designed to study 2,4-disubstituted 6-fluoroquinolines as antiplasmodial agents by using in silico techniques, to aid in the design of novel analogs with high potency against malaria and high inhibition of Plasmodium falciparum translation elongation factor 2 (PfeEF2), a novel drug target.MethodsQuantitative structure-activity relationships (QSAR) of 2,4-disubstituted 6-fluoroquinolines were studied with the genetic function approximation technique in Material Studio software. The 3D structure of PfeEF2 was modeled in the SWISS-MODEL workspace through homology modeling. A molecular docking study of the modeled PfeEF2 and 2,4-disubstituted 6-fluoroquinolines was conducted with Autodock Vina in Pyrx software. Furthermore, the in silico pharmacokinetic properties of selected compounds were investigated.ResultsA robust, reliable and predictive QSAR model was developed that related the chemical structures of 2,4-disubstituted 6-fluoroquinolines to their antiplasmodium activities. The model had an internal squared correlation coefficient R2 of 0.921, adjusted squared correlation coefficient R2adj of 0.878, leave-one-out cross-validation coefficient Q2cv of 0.801 and predictive squared correlation coefficient R2pred of 0.901. The antiplasmodium activity of 6-fluoroquinolines was found to depend on the n5Ring, GGI9, TDB7u, TDB8u and RDF75i physicochemical properties: n5Ring, TDB8u and RDF75i were positively associated, whereas GGI9 and TDB7u were negatively associated, with the antiplasmodium activity of the compounds. Stable complexes formed between the compounds and modeled PfeEF2, with binding affinity ranging from -8.200 to -10.700 kcal/mol. Compounds 5, 11, 16, 22 and 24 had better binding affinities than quinoline-4-carboxamide (DDD107498), as well as good pharmacokinetic properties, and therefore may be better inhibitors of this novel target.ConclusionQSAR and docking studies provided insight into designing novel 2,4-disubstituted 6-fluoroquinolines with high antiplasmodial activity and good structural properties for inhibiting a novel antimalarial drug target.

Project description:The ABCB1 transporter also known as P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette super-family of transporters; it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping the compounds out of cells. P-gp contributes to a decrease of toxicity and possesses broad substrate specificity. It is involved in the failure of numerous anticancer and antiviral chemotherapies due to the multidrug resistance (MDR) phenomenon, where it removes the chemotherapeutics out of the targeted cells. Understanding the details of the ligand-P-gp interaction is therefore crucial for the development of drugs that might overcome the MRD phenomenon and for obtaining a more effective prediction of the toxicity of certain compounds. In this work, an in silico modeling was performed using homology modeling and molecular docking methods with the aim of better understanding the ligand-P-gp interactions. Based on different mouse P-gp structural templates from the PDB repository, a 3D model of the human P-gp (hP-gp) was constructed by means of protein homology modeling. The homology model was then used to perform molecular docking calculations on a set of thirteen compounds, including some well-known compounds that interact with P-gp as substrates, inhibitors, or both. The sum of ranking differences (SRD) was employed for the comparison of the different scoring functions used in the docking calculations. A consensus-ranking scheme was employed for the selection of the top-ranked pose for each docked ligand. The docking results showed that a high number of π interactions, mainly π-sigma, π-alkyl, and π-π type of interactions, together with the simultaneous presence of hydrogen bond interactions contribute to the stability of the ligand-protein complex in the binding site. It was also observed that some interacting residues in hP-gp are the same when compared to those observed in a co-crystallized ligand (PBDE-100) with mouse P-gp (PDB ID: 4XWK). Our in silico approach is consistent with available experimental results regarding P-gp efflux transport assay; therefore it could be useful in the prediction of the role of new compounds in systemic toxicity.

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Homology modeling and docking studies of ENPP4: a BCG activated tumoricidal macrophage protein.

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Homology modeling and docking studies of ENPP4: a BCG activated tumoricidal macrophage protein.

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