Isfahan University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Targeting and Ultrabroad Insight Into Molecular Basis of Resistance-Nodulation-Cell Division Efflux Pumps Publisher Pubmed



Seyedhosseini Ghaheh H1 ; Damavandi MS2 ; Sadeghi P2, 3 ; Massah AR4 ; Asl TH5 ; Salarijazi A3 ; Hejazi SH5
Authors
Show Affiliations
Authors Affiliations
  1. 1. Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Drug Development and Innovation, Behban Pharmed Lotus, Tehran, Iran
  4. 4. Department of Chemistry, Shahreza Branch, Islamic Azad University, P.O. Box 311-86145, Shahreza, Isfahan, Iran
  5. 5. Skin Diseases and Leishmaniasis Research Center, Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Source: Scientific Reports Published:2022


Abstract

Resistance-nodulation-cell devision (RND) efflux pump variants have attracted a great deal of attention for efflux of many antibiotic classes, which leads to multidrug-resistant bacteria. The present study aimed to discover the interaction between the RND efflux pumps and antibiotics, find the conserved and hot spot residues, and use this information to target the most frequent RND efflux pumps. Protein sequence and 3D conformational alignments, pharmacophore modeling, molecular docking, and molecular dynamics simulation were used in the first level for discovering the function of the residues in interaction with antibiotics. In the second level, pharmacophore-based screening, structural-based screening, multistep docking, GRID MIF, pharmacokinetic modeling, fragment molecular orbital, and MD simulation were utilized alongside the former level information to find the most proper inhibitors. Five conserved residues, containing Ala209, Tyr404, Leu415, Asp416, and Ala417, as well as their counterparts in other OMPs were evaluated as the crucial conserved residues. MD simulation confirmed that a number of these residues had a key role in the performance of the efflux antibiotics; therefore, some of them were hot spot residues. Fourteen ligands were selected, four of which interacted with all the crucial conserved residues. NPC100251 was the fittest OMP inhibitor after pharmacokinetic computations. The second-level MD simulation and FMO supported the efficacy of the NPC100251. It was exhibited that perhaps OMPs worked as the intelligent and programable protein. NPC100251 was the strongest OMPs inhibitor, and may be a potential therapeutic candidate for MDR infections. © 2022, The Author(s).
Related Docs
View other Related Docs
1. Discovery of Potential Inhibitors Against New Delhi Metallo-Β-Lactamase-1 From Natural Compounds: In Silico-Based Methods, Scientific Reports (2021)
2. Bioinformatic Screening of Compounds From Iranian Lamiaceae Family Members Against Sars-Cov-2 Spike Protein, Letters in Drug Design and Discovery (2023)
3. Theoretical Studies of 1,4-Dihydropyridine-3,5-Dicarboxamides As Possible Inhibitors of Mycobacterium Tuberculosis Enoyl Reductase, Monatshefte fur Chemie (2012)
4. Identification of Novel 3-Hydroxy-Pyran-4-One Derivatives As Potent Hiv-1 Integrase Inhibitors Using in Silico Structure-Based Combinatorial Library Design Approach, Frontiers in Chemistry (2019)
5. Evaluation of Chlorogenic Acid and Carnosol for Anti-Efflux Pump and Anti-Biofilm Activities Against Extensively Drug-Resistant Strains of Staphylococcus Aureus and Pseudomonas Aeruginosa, Microbiology Spectrum (2024)
6. Novel Mutation in Efflux Pump Rv1258c (Tap) Gene in Drug Resistant Clinical Isolates of Mycobacterium Tuberculosis in Iran, Journal of Infection in Developing Countries (2024)
7. New 3-Hydroxypyridine-4-One Analogues: Their Synthesis, Antimicrobial Evaluation, Molecular Docking, and in Silico Adme Prediction, Medicinal Chemistry (2024)
8. Towards Screening and Repurposing of Approved Drugs for the Treatment of Covid-19 Using Molecular Docking, Physical Chemistry Research (2023)
Experts (# of related papers)
View all Related Experts
Afshin Fassihi (13)
Lotfollah Saghaie Dehkordi (7)
Other Related Docs
9. Sequence-Based Detection of First-Line and Second-Line Drugs Resistance-Associated Mutations in Mycobacterium Tuberculosis Isolates in Isfahan, Iran, Infection, Genetics and Evolution (2020)
10. Computational Design of a Potential Therapeutic Peptide Against Spike Protein of Sars-Cov-2, Journal of Computational Biophysics and Chemistry (2021)
11. A Quantitative Structure-Activity Relationship (Qsar) Study of Some Diaryl Urea Derivatives of B-Raf Inhibitors, Research in Pharmaceutical Sciences (2016)
12. Insights Into the Human A1 Adenosine Receptor From Molecular Dynamics Simulation: Structural Study in the Presence of Lipid Membrane, Medicinal Chemistry Research (2015)
13. Discovery of Novel Direct Small-Molecule Inhibitors Targeting Hif-2Α Using Structure-Based Virtual Screening, Molecular Dynamics Simulation, and Mm-Gbsa Calculations, Molecular Diversity (2024)
14. Exploring a Model of a Chemokine Receptor/Ligand Complex in an Explicit Membrane Environment by Molecular Dynamics Simulation: The Human Ccr1 Receptor, Journal of Chemical Information and Modeling (2011)
15. Preparing a Database of Corrected Protein Structures Important in Cell Signaling Pathways, Research in Pharmaceutical Sciences (2023)
16. Gp41 Inhibitory Activity Prediction of Theaflavin Derivatives Using Ligand/Structure-Based Virtual Screening Approaches, Computational Biology and Chemistry (2019)
17. Investigating the Antibiotic Resistance Prevalence and Phenotypic and Genotypic Evaluation of Acrab-Oprm Efflux Pump in Multidrug-Resistant in Clinical Isolates of Moraxella Catarrhalis in Kazerun City, Iran, Iranian Journal of Medical Microbiology (2020)
18. Determination of the Efflux Pump-Mediated Resistance Prevalence in Pseudomonas Aeruginosa, Using an Efflux Pump Inhibitor, Current Microbiology (2009)
19. Molecular Modelling Study on Pyrrolo[2,3-B]Pyridine Derivatives As C-Met Kinase Inhibitors: A Combined Approach Using Molecular Docking, 3D-Qsar Modelling and Molecular Dynamics Simulation, Molecular Simulation (2020)
20. In Silico Activity of As1411 Aptamer Against Nucleolin of Cancer Cells, Iranian Journal of Blood and Cancer (2020)
21. Biological Evaluation, Docking and Molecular Dynamic Simulation of Some Novel Diaryl Urea Derivatives Bearing Quinoxalindione Moiety, Research in Pharmaceutical Sciences (2017)
22. Homology Modeling of Human Ccr5 and Analysis of Its Binding Properties Through Molecular Docking and Molecular Dynamics Simulation, Biochimica et Biophysica Acta - Biomembranes (2011)
23. In Silico Design of Novel Fak Inhibitors Using Integrated Molecular Docking, 3D-Qsar and Molecular Dynamics Simulation Studies, Journal of Biomolecular Structure and Dynamics (2022)
24. 3D-Qsar, Molecular Docking, and Molecular Dynamic Simulations for Prediction of New Hsp90 Inhibitors Based on Isoxazole Scaffold, Journal of Biomolecular Structure and Dynamics (2018)
25. Effect of Biomolecular Conformation on Docking Simulation: A Case Study on a Potent Hiv-1 Protease Inhibitor, Iranian Journal of Pharmaceutical Research (2015)
26. Discovery of Novel Rarα Agonists Using Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation Studies, PLoS ONE (2023)
27. Novel Aldimine-Type Schiff Bases of 4-Amino-5-[(3,4,5-Trimethoxyphenyl)Methyl]-1,2,4-Triazole-3-Thione/Thiol: Docking Study, Synthesis, Biological Evaluation, and Anti-Tubulin Activity, Archiv der Pharmazie (2016)
28. Structural Analysis of Some Pyrrolopyrimidine Derivatives and Examining Their Binding Affinity Against the Cyclooxygenase-2 Enzyme, Turkish Computational and Theoretical Chemistry (2021)
29. Computer-Aided Design of Novel Antibacterial 3-Hydroxypyridine-4-Ones: Application of Qsar Methods Based on the Molmap Approach, Journal of Computer-Aided Molecular Design (2012)