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.

Friends or foes? Novel antimicrobials tackling MDR/XDR Gram-negative bacteria: a systematic review

“…Nevertheless, the field of molecular science has been in constant evolution and novel approaches have shown promising results. One example of these is the development of dendrimers, nanosized molecules previously researched for cancer treatment, which have recently been tested for antimicrobial activity via PBP affinity, showcasing promising results (Ahmed et al, 2016). Their silver salt structures have been increasingly studied in order to produce updated molecules, with improved MIC reduction capabilities, via elevated cationic characteristics through extra amino acid conjugation (Schito et al, 2021).…”

Interactions of dendrimers with biological drug targets: reality or mystery – a gap in drug delivery and development research

“…A recently reported study on an in silico evaluation of some poly( propyl ether imine) (PETIM) dendrimer's binding affinity to penicillin binding proteins (PBPs) by our research group was an initiation to bridge this scientific gap, and provided some clues for understanding the molecular mechanism behind the antibacterial activity of dendrimers. 47 We assume that a lack of guidance on integrating molecular and material modelling tools that are available using various molecular modelling platforms is one of the major obstacles for advancement in this field of study. Therefore, the present article is an effort to review a number of modelling guidelines for members of the scientific community who are interested in the rational design and development of dendrimers as materials in general, and as medicinal agents in particular.…”