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Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies.
Infect Genet Evol. 2020 Jul 01; 85:104448.IG

Abstract

Pseudomonas aeruginosa has become a global concern due to its extreme resistance to most of the last resort antibiotics. Present study focuses on the screening of potential molecular targets involved in regulation of biofilm formation in P. aeruginosa and identification of potential natural lead molecules against these targets by molecular modelling, docking and simulation studies. Response regulator (GacA) and transcriptional activator (RhlR) involved in biofilm formation in P. aeruginosa were identified as molecular targets by metabolic pathway analysis and the three dimensional structures of these proteins were predicted by homology modelling and validated. By thorough literature survey, 78 lead molecules were screened and their pharmacokinetic profiles were determined and best two of them selected. The binding potential of selected lead molecules against GacA and RhlR were predicted by molecular docking and their binding energy was compared with the interaction of meropenem and its usual target penicillin binding protein-3. The stabilities of best docked complex were studied by molecular dynamic (MD) simulation. This study showed that Celastrol present in Celastrus paniculatus and Rotiorinol present in Chaetomium cupreum showed better binding affinities with GacA (binding energy -7.2 kcal/mol) and RhlR (binding energy -8.0 kcal/mol) respectively in comparison with the binding of Meropenem and its target (binding energy -6.2 kcal/mol). MD simulation studies showed that GacA-Celastrol and RhlR-Rotiorinol complexes demonstrated conformational stability throughout the simulation. This study highlights the application of GacA and RhlR as prospective targets and Celastrol and Rotiorinol are the potential lead molecules towards biofilm producing drug resistant P. aeruginosa.

Authors+Show Affiliations

Department of Microbiology, St. Pius X College Rajapuram, Kasaragod, Kerala, India. Electronic address: sinoshmicro@stpius.ac.in.Department of Biotechnology, Dayananda Sagar College of Engineering, Kumaraswamy Layout, Bengaluru, India.Department of Biotechnology, Dayananda Sagar College of Engineering, Kumaraswamy Layout, Bengaluru, India.Department of Biotechnology, RV College of Engineering, Bengaluru, Karnataka, India.Department of Biotechnology, RV College of Engineering, Bengaluru, Karnataka, India.Department of Biotechnology, Dayananda Sagar College of Engineering, Kumaraswamy Layout, Bengaluru, India.Department of Biotechnology, RV College of Engineering, Bengaluru, Karnataka, India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32622078

Citation

Skariyachan, Sinosh, et al. "Response Regulator GacA and Transcriptional Activator RhlR Proteins Involved in Biofilm Formation of Pseudomonas Aeruginosa Are Prospective Targets for Natural Lead Molecules: Computational Modelling, Molecular Docking and Dynamic Simulation Studies." Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases, vol. 85, 2020, p. 104448.
Skariyachan S, Ravishankar R, Gopal D, et al. Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies. Infect Genet Evol. 2020;85:104448.
Skariyachan, S., Ravishankar, R., Gopal, D., Muddebihalkar, A. G., Uttarkar, A., Praveen, P. K. U., & Niranjan, V. (2020). Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies. Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases, 85, 104448. https://doi.org/10.1016/j.meegid.2020.104448
Skariyachan S, et al. Response Regulator GacA and Transcriptional Activator RhlR Proteins Involved in Biofilm Formation of Pseudomonas Aeruginosa Are Prospective Targets for Natural Lead Molecules: Computational Modelling, Molecular Docking and Dynamic Simulation Studies. Infect Genet Evol. 2020 Jul 1;85:104448. PubMed PMID: 32622078.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies. AU - Skariyachan,Sinosh, AU - Ravishankar,Roshini, AU - Gopal,Dharshini, AU - Muddebihalkar,Aditi G, AU - Uttarkar,Akshay, AU - Praveen,Prinith Kaveramma Uluvangada, AU - Niranjan,Vidya, Y1 - 2020/07/01/ PY - 2020/04/29/received PY - 2020/06/21/revised PY - 2020/06/25/accepted PY - 2020/7/6/pubmed PY - 2020/7/6/medline PY - 2020/7/5/entrez KW - Biofilm formation KW - Celastrol KW - Computational virtual screening KW - Potential natural lead molecules KW - Pseudomonas aeruginosa KW - Response regulator (GacA) KW - Rotiorinol KW - Transcriptional activator (RhlR) SP - 104448 EP - 104448 JF - Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases JO - Infect. Genet. Evol. VL - 85 N2 - Pseudomonas aeruginosa has become a global concern due to its extreme resistance to most of the last resort antibiotics. Present study focuses on the screening of potential molecular targets involved in regulation of biofilm formation in P. aeruginosa and identification of potential natural lead molecules against these targets by molecular modelling, docking and simulation studies. Response regulator (GacA) and transcriptional activator (RhlR) involved in biofilm formation in P. aeruginosa were identified as molecular targets by metabolic pathway analysis and the three dimensional structures of these proteins were predicted by homology modelling and validated. By thorough literature survey, 78 lead molecules were screened and their pharmacokinetic profiles were determined and best two of them selected. The binding potential of selected lead molecules against GacA and RhlR were predicted by molecular docking and their binding energy was compared with the interaction of meropenem and its usual target penicillin binding protein-3. The stabilities of best docked complex were studied by molecular dynamic (MD) simulation. This study showed that Celastrol present in Celastrus paniculatus and Rotiorinol present in Chaetomium cupreum showed better binding affinities with GacA (binding energy -7.2 kcal/mol) and RhlR (binding energy -8.0 kcal/mol) respectively in comparison with the binding of Meropenem and its target (binding energy -6.2 kcal/mol). MD simulation studies showed that GacA-Celastrol and RhlR-Rotiorinol complexes demonstrated conformational stability throughout the simulation. This study highlights the application of GacA and RhlR as prospective targets and Celastrol and Rotiorinol are the potential lead molecules towards biofilm producing drug resistant P. aeruginosa. SN - 1567-7257 UR - https://www.unboundmedicine.com/medline/citation/32622078/Response_regulator_GacA_and_transcriptional_activator_RhlR_proteins_involved_in_biofilm_formation_of_Pseudomonas_aeruginosa_are_prospective_targets_for_natural_lead_molecules:_Computational_modelling,_molecular_docking_and_dynamic_simulation_studies L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-1348(20)30279-3 DB - PRIME DP - Unbound Medicine ER -
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