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In-silico characterization of ?-(1, 3)-endoglucanase (ENGL1) from Aspergillus fumigatus by homology modeling and docking studies.

ABSTRACT: During the past few years a significant rise in aspergillosis caused by filamentous fungus Aspergillus fumigatus has been recorded particularly in immunocompromised patients. At present, there are limited numbers of antifungal agents to combat these infections and the situation has become more complex due to emergence of antifungal resistance and side-effects of antifungal drugs. These situations have increased the demand for novel drug targets. Recent studies have revealed that the ?-1,3-endoglucanase (ENGL1) plays an essential role in cell wall remodeling that is absolutely required during growth and morphogenesis of filamentous fungi and thus is a promising target for the development of antifungal agents. Unfortunately no structural information of fungal ?- glucanases has yet been available in the Protein Databank (PDB). Therefore in the present study, 3D structure of ?-(1,3)- endoglucanase (ENGL1) was modeled by using I-TASSER server and validated with PROCHECK and VERIFY 3D. The best model was selected, energy minimized and used to analyze structure function relationship with substrate ?-(1,3)-glucan by C-DOCKER (Accelrys DS 2.0). The results indicated that amino acids (GLU 380, GLN 383, ASP 384, TYR 395, SER 712, and ARG 713) present in ?-1,3-endoglucanase receptor are of core importance for binding activities and these residues are having strong hydrogen bond interactions with ?-(1,3)-glucan. The predicted model and docking studies permits initial inferences about the unexplored 3D structure of the ?-(1,3)-endoglucanase and may be promote in relational designing of molecules for structure-function studies.

SUBMITTER: Ahmed R

PROVIDER: S-EPMC3796880 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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in-silico characterization of β-(1, 3)-endoglucanase (ENGL1) from Aspergillus fumigatus by homology modeling and docking studies.

Ahmed Rizwan R Jain Swatantra Kumar SK Shukla Praveen Kumar PK

Bioinformation 20130923 16

During the past few years a significant rise in aspergillosis caused by filamentous fungus Aspergillus fumigatus has been recorded particularly in immunocompromised patients. At present, there are limited numbers of antifungal agents to combat these infections and the situation has become more complex due to emergence of antifungal resistance and side-effects of antifungal drugs. These situations have increased the demand for novel drug targets. Recent studies have revealed that the β-1,3-endogl ...[more]

PMID: 24143049

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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.

Dataset Information

In-silico characterization of ?-(1, 3)-endoglucanase (ENGL1) from Aspergillus fumigatus by homology modeling and docking studies.

Publications

in-silico characterization of β-(1, 3)-endoglucanase (ENGL1) from Aspergillus fumigatus by homology modeling and docking studies.

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