Theoretical and Computational Chemistry

Droperidol as a Potential Inhibitor of Acyl-homoserine Lactone Synthase from A. baumannii: Insights from Virtual Screening, MD Simulations and MM/PBSA Calculations



A. baumannii belongs to the ESKAPE family of pathogens and is a multi-drug resistant, gram-negative bacteria which follows the anaerobic form of respiration. A. baumannii is known to be the causative agent of hospital-related infections such as pneumonia, meningitis, endocarditis, septicaemia and a plethora of infections such as urinary tract and wound infections found primarily in immunocompromised patients. These attributes of A. baumannii make it a priority pathogen against which potential therapeutic agents need to be developed. A. baumannii employs the formation of a biofilm to insulate its colonies from the outer environment, which allows it to grow under harsh environmental conditions and develop resistance against various drug molecules. Acyl-homoserine lactone synthase (AHLS) is an enzyme involved in the quorum-sensing pathway in A. baumannii, which is responsible for the synthesis of signal molecules known as acyl-homoserine lactones (AHL), which trigger the signalling pathway to regulate the factors involved in biofilm formation and regulation. The current study utilised a homology modeled structure of AHLS to virtually screen it against the ZINC in trial/FDA approved drug molecule library to find a subset of potential lead molecules. These molecules were then filtered based on Lipinski’s, toxicological and ADME properties, binding affinity, and interaction patterns to delineate lead molecules, which were then validated using molecular docking. The identified molecules and a control molecule were subsequently subjected to molecular dynamics simulations to mimic physiological conditions of protein-ligand binding under the influence of a forcefield. The MM/PBSA based binding free energy calculations showed favourable results for Droperidol (-50.02 ± 4.67 kcal/mol) and Cipargamin (-42.29 ± 4.05 kcal/mol). The global and essential dynamics analyses, free energy landscape and dynamical cross-correlation matrix and MM/PBSA based binding free energy suggested Droperidol (ZINC000019796080) and Cipargamin (ZINC000049037032) as potential inhibitors against the acylated-ACP substrate-binding site in AHLS from A. baumannii.


Thumbnail image of Final AHLS Manuscript.pdf