Identification of Novel PBP2B Protein Inhibitors against Streptococcus pneumoniae in Marine Natural Products using an In-Silico Approach
Authors: Chandrasekar Karthickeyan , Subbiah Parthasarathy 
Published: August 2024

Background:
The aim of this research is to identify marine natural compounds derived
from green, red, and brown algae that might possibly inhibit the Penicillin-Binding Proteins (PBPs)
protein, which is responsible for the development of antibiotic resistance in Streptococcus pneumoniae
(mutated resistant 5204-PBP2B strain). We obtained this by using virtual screening and
molecular docking. In AutoDock Vina and the Schrodinger suite software, we screened a library
of marine natural chemicals and discovered four intriguing candidates that had strong binding
affinities to the active region of the PBPs protein. Based on our findings, four naturally occurring
marine chemicals show great promise as new inhibitors of S. pneumoniae 5204-PBP2B protein.
These discoveries reveal important new information on the potential application of marine natural
products as a source of new drugs to combat antibiotic resistance in Streptococcus pneumoniae
and other bacterial infections.

Methods:
The 3318 compounds in the Comprehensive Marine Natural Products Database (CMNPD)
derived from green algae (293 compounds), brown algae (1212 compounds) and red algae
(1813 compounds) were taken into consideration for this study. Through virtual screening and
molecular docking investigations, we found the optimum compounds for the Penicillin-Binding
Proteins (PBPs) protein in Streptococcus pneumoniae. Utilizing AutoDock Vina and Schrodinger
Suite software, the 5204-PBP2B protein selected for this investigation was examined. The structure
and binding interaction have been displayed using PyMOL software.

Results:
Through virtual screening and molecular docking investigations for the 5204-PBP2B protein
in Streptococcus pneumoniae, we were able to identify four marine natural products that are
present in brown algae from the Comprehensive Marine Natural Products Database.

Conclusion:
The study has indicated that the main cause of bacterial resistance to antibiotics is
5204-PBP2B in S. pneumoniae. This study's methodology has been shown to be effective in identifying
four strong inhibitors of the CMNPD. In this work, potent molecules from CMNPD compounds
were screened using the 3D structure of mutated resistant 5204 strain, named 5204-
PBP2B (PDB ID: 2WAE) of S. pneumoniae. Out of 3318 compounds that showed strong interactions
with PBP2B, docking studies revealed that four of the compounds were inhibitory for the
protein and could be used to treat PBP2B. These four marine products were selected as a result of
our earlier research on Klebsiella pneumonia’s New Delhi metallo-β-lactamase-1 (NDM-1) protein.
This study thus reveals the importance of marine natural products for improving the drug development
process, as well as the ability of four marine products generated from brown algae to inhibit
both the NDM-1 protein of Klebsiella pneumoniae and the 5204-PBP2B protein in Streptococcus
pneumoniae. It is also possible to expand this approach by investigating how different receptor
inhibitors interact in a lab setting. Potential inhibitors can be discovered by evaluating the
biological activity of the drugs and applying virtual screening and molecular docking techniques.