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Please use this identifier to cite or link to this item: http://repository.iitr.ac.in/handle/123456789/20223
Title: Structure-Based Identification of Potential Drugs Against FmtA of Staphylococcus aureus: Virtual Screening, Molecular Dynamics, MM-GBSA, and QM/MM
Authors: Dalal V.
Dhankhar P.
Singh V.
Singh V.
Rakhaminov G.
Golemi-Kotra D.
Kumar, Pravindra R.Manish
Published in: Protein Journal
Abstract: Staphylococcus aureus is resistant to β-lactam antibiotics and causes several skin diseases to life-threatening diseases. FmtA is found to be one of the main factors involved in methicillin resistance in S. aureus. FmtA exhibits an esterase activity that removes the D-Ala from teichoic acid. Teichoic acids played a significant role in cell wall synthesis, cell division, colonization, biofilm formation, virulence, antibiotic resistance, and pathogenesis. The virtual screening of drug molecules against the crystal structure of FmtA was performed and the binding affinities of top three molecules (ofloxacin, roflumilast, and furazolidone) were predicted using molecular docking. The presence of positive potential and electron affinity regions in screened drug molecules by DFT analysis illustrated that these molecules are reactive in nature. The protein–ligand complexes were subjected to molecular dynamics simulation. Molecular dynamics analysis such as RMSD, RMSF, Rg, SASA, PCA, and FEL results suggested that FmtA-drug(s) complexes are stable. MM-GBSA binding affinity and QM/MM results (ΔG, ΔH, and ΔS) revealed that active site residues (Ser127, Lys130, Tyr211, Asp213, and Asn343) of FmtA played an essential for the binding of the drug(s) to form a lower energy stable protein–ligand complexes. FmtAΔ42 was purified using cation exchange and gel filtration chromatography. Fluorescence spectroscopy and circular dichroism results showed that interactions of drugs with FmtAΔ42 affect the tertiary structure and increase the thermostability of the protein. The screened molecules need to be tested and could be further modified to develop the antimicrobial compounds against S. aureus. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
Citation: Protein Journal, 40(2): 148-165
URI: https://doi.org/10.1007/s10930-020-09953-6
http://repository.iitr.ac.in/handle/123456789/20223
Issue Date: 2021
Publisher: Springer
Keywords: FmtA
Molecular dynamics simulation
Molecular mechanics generalized born surface area (MM-GBSA)
Our own N-layered integrated molecular orbital and molecular mechanics (ONIOM)
Staphylococcus aureus
ISSN: 15723887
Author Scopus IDs: 57194227044
57214114755
57220825344
57220825344
57210330669
6507129845
55064809000
Author Affiliations: Dalal, V., Department of Biotechnology, IIT Roorkee, Roorkee, Uttrakhand 247667, India
Dhankhar, P., Department of Biotechnology, IIT Roorkee, Roorkee, Uttrakhand 247667, India
Singh, V., Department of Biotechnology, IIT Roorkee, Roorkee, Uttrakhand 247667, India, Department of Biotechnology, IIT Roorkee, Roorkee, Uttrakhand 247667, India
Singh, V., Department of Biotechnology, IIT Roorkee, Roorkee, Uttrakhand 247667, India, Department of Biotechnology, IIT Roorkee, Roorkee, Uttrakhand 247667, India
Rakhaminov, G., Department of Biology, York University, 4700 Keele Street, Toronto, Canada
Golemi-Kotra, D., Department of Biology, York University, 4700 Keele Street, Toronto, Canada
Kumar, P., Department of Biotechnology, IIT Roorkee, Roorkee, Uttrakhand 247667, India
Funding Details: PK acknowledges the Council of Scientific and Industrial Research (CSIR) for financial support (Project Ref. Number CSR-1459-BIO). VD, PD, VS, and VS thanks the Department of Biotechnology [DBT/2015/IIT-R/349], Ministry of Human Resource Development, Indian Council of Medical Research (ICMR), and University Grant Commission for financial support. We are thankful to the Department of chemistry, IIT Roorkee, to provide the Gaussian software. Authors thank Macromolecular Crystallographic Unit (MCU), a Central Facility at Institute Instrumentation Centre (IIC), IIT Roorkee, for computational work. Authors acknowledge Prof. Shailly Tomar, IIT Roorkee, for providing the computational facility. Department of Biotechnology, Ministry of Science and Technology, India, DBT: DBT/2015/IIT-R/349; Indian Council of Medical Research, ICMR; Council of Scientific and Industrial Research, India, CSIR: CSR-1459-BIO; University Grants Commission, UGC; Indian Institute of Technology Roorkee, IITR; Ministry of Human Resource Development, MHRD; Bangladesh Council of Scientific and Industrial Research, BCSIR
Corresponding Author: Kumar, P.; Department of Biotechnology, India; email: pravindra.kumar@bt.iitr.ac.in
Appears in Collections:Journal Publications [BT]

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