title: In Silico Characterization of the Binding Affinity of Dendrimers to Penicillin-Binding Proteins (PBPs): Can PBPs be Potential Targets for Antibacterial Dendrimers?
abstract: We have shown that novel silver salts of poly (propyl ether) imine (PETIM) dendron and dendrimers developed in our group exhibit preferential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule, explore the mechanism of binding with biological targets, and explain their preferential antibacterial activity. The current article reports the conformational landscape as well as mechanism of binding of generation 1 PETIM dendron and dendrimers to penicillin-binding proteins (PBPs) in order to understand the antibacterial activity profiles of their silver salts. Molecular dynamics at different simulation protocols and conformational analysis were performed to elaborate on the conformational features of the studied dendrimers, as well as to create the initial structure for further binding studies. The results showed that for all compounds, there were no significant conformational changes due to variation in simulation conditions. Molecular docking calculations were performed to investigate the binding theme between the studied dendrimers and PBPs. Interestingly, in significant accordance with the experimental data, dendron and dendrimer with aliphatic cores were found to show higher activity against S. aureus than the dendrimer with an aromatic core. The latter showed higher activity against MRSA. The findings from this computational and molecular modeling report together with the experimental results serve as a road map toward designing more potent antibacterial dendrimers against resistant bacterial strains.
authors.affiliation: Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, KwaZulu-Natal, South Africa.
authors.forename: Shaimaa
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, KwaZulu-Natal, South Africa.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Vepuri
authors.affiliation: Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, KwaZulu-Natal, South Africa.
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Ramesh
authors.affiliation: Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, KwaZulu-Natal, South Africa.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kalhapure
authors.affiliation: Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, KwaZulu-Natal, South Africa.
authors.forename: Nadia
authors.initials: N
authors.lastname: Suleman
authors.affiliation: Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban, 4000, KwaZulu-Natal, South Africa. GOVENDERTH@ukzn.ac.za.
authors.forename: Thirumala
authors.initials: T
authors.lastname: Govender
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D046915:Penicillin-Binding Proteins / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D050091:Dendrimers; D046915:Penicillin-Binding Proteins; C000607946:polypropyletherimine dendrimer glucosamine; D005944:Glucosamine
keywords: Antibacterial resistance; Binding analysis; Dendrimers; Molecular dynamics; Penicillin-binding proteins