TY - JOUR
T1 - Energy-optimized pharmacophore coupled virtual screening in the discovery of quorum sensing inhibitors of LasR protein of Pseudomonas aeruginosa
AU - Nain, Zulkar
AU - Sayed, Sifat Bin
AU - Karim, Mohammad Minnatul
AU - Islam, Md Ariful
AU - Adhikari, Utpal Kumar
PY - 2020
Y1 - 2020
N2 - Pseudomonas aeruginosa is an emerging opportunistic pathogen responsible for cystic fibrosis and nosocomial infections. In addition, empirical treatments are become inefficient due to their multiple-antibiotic resistance and extensive colonizing ability. Quorum sensing (QS) plays a vital role in the regulation of virulence factors in P. aeruginosa. Therefore, attenuation of virulence by QS inhibition could be an alternative and effective approach to control the infections. In this study, we sought to discover new QS inhibitors (QSIs) against LasR receptor in P. aeruginosa using chemoinformatics. Initially, a structure-based high-throughput virtual screening was performed using the LasR active site that identified 61404 relevant molecules. The e-pharmacophore (ADAHH) screening of these molecules rendered 72 QSI candidates. In standard-precision docking, only 7 compounds were found as potential QSIs based on their higher binding affinity to LasR receptor (−7.53 to −10.32 kcal/mol compared to −7.43 kcal/mol of native ligand). The ADMET properties of these compounds were suitable to be QSIs. Later, extra-precision docking and binding energy calculation suggested ZINC19765885 and ZINC72387263 as the most promising QSIs. The dynamic simulation of the docked complexes showed stable binding affinity and molecular interactions. The current study suggested that these two compounds could be used in P. aeruginosa QS inhibition to combat bacterial infections. Communicated by Ramaswamy H. Sarma.
AB - Pseudomonas aeruginosa is an emerging opportunistic pathogen responsible for cystic fibrosis and nosocomial infections. In addition, empirical treatments are become inefficient due to their multiple-antibiotic resistance and extensive colonizing ability. Quorum sensing (QS) plays a vital role in the regulation of virulence factors in P. aeruginosa. Therefore, attenuation of virulence by QS inhibition could be an alternative and effective approach to control the infections. In this study, we sought to discover new QS inhibitors (QSIs) against LasR receptor in P. aeruginosa using chemoinformatics. Initially, a structure-based high-throughput virtual screening was performed using the LasR active site that identified 61404 relevant molecules. The e-pharmacophore (ADAHH) screening of these molecules rendered 72 QSI candidates. In standard-precision docking, only 7 compounds were found as potential QSIs based on their higher binding affinity to LasR receptor (−7.53 to −10.32 kcal/mol compared to −7.43 kcal/mol of native ligand). The ADMET properties of these compounds were suitable to be QSIs. Later, extra-precision docking and binding energy calculation suggested ZINC19765885 and ZINC72387263 as the most promising QSIs. The dynamic simulation of the docked complexes showed stable binding affinity and molecular interactions. The current study suggested that these two compounds could be used in P. aeruginosa QS inhibition to combat bacterial infections. Communicated by Ramaswamy H. Sarma.
KW - Pseudomonas aeruginosa
KW - bacterial diseases
KW - quorum sensing (microbiology)
KW - virulence (microbiology)
UR - http://hdl.handle.net/1959.7/uws:55729
U2 - 10.1080/07391102.2019.1700168
DO - 10.1080/07391102.2019.1700168
M3 - Article
SN - 0739-1102
VL - 38
SP - 5374
EP - 5388
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 18
ER -