In Silico Identification of Novel PrfA Inhibitors to Fight Listeriosis: A Virtual Screening and Molecular Dynamics Studies

Listeria monocytogenes is considered to be one of the most dangerous foodborne pathogens as it can cause listeriosis, a life-threatening human disease. While the incidence of listeriosis is very low its fatality rate is exceptionally high. Because many multi-resistance Listeria monocytogenes strains that do not respond to conventional antibiotic therapy have been recently described, development of new antimicrobials to fight listeriosis is necessary. The positive regulatory factor A (PrfA) is a key homodimeric transcription factor that modulates the transcription of multiple virulence factors which are ultimately responsible of Listeria monocytogenes’ pathogenicity. In the present manuscript we describe several new potential PrfA inhibitors that were identified after performing ligand-based virtual screening followed by structure-based virtual screening against the wild-type PrfA structure. The three top-scored drug-likeness inhibitors bound to the wild-type PrfA structure were further assessed by Molecular Dynamics simulations. Besides, the three top-scored inhibitors were docked into a constitutive active apoPrfA mutant structure and the corresponding complexes were also simulated. According to the obtained data, PUBChem 87534955 (P875) and PUBChem 58473762 (P584) may not only bind and inhibit wild-type PrfA but the aforementioned apoPrfA mutant as well. Therefore, P875 and P584 might represent good starting points for the development of a completely new set of antimicrobial agents to treat listeriosis. ### Competing Interest Statement The authors have declared no competing interest. * 2OG : 2-oxoglutarate C01 : Compound 01 C16 : Compound 16 CO : Carbon monoxide cAMP : 3’,5’-cyclic adenosin monophosphate DNA : Deoxyribonucleotide Acid GSH : Reduced Gluthatione HLH : Helix-Loop-Helix INSERM : French National Institute of Health and Medical Research LBVS : Ligand-Based Virtual Screening MD : Molecular Dynamics ns : nanosecond OCPA : 3-chloro-4-hydroxyphenylacetic acid P875 : PUBChem 87534955 P100 : PUBChem 100988414 P584 : PUBChem 58473762 PCA : Principal Component Analysis PDB : Protein Data Bank PDBQT : Protein Data Bank Partial Charge (Q) and atom type (T) PRFA : Positive Regulatory Factor A RG : Radius of Gyration RMSD : Root Mean Standard Deviation SDF : Standard Database Format SBVS : Structure-Based Virtual Screening USR : Ultrafast Shaper Recognition USRCAT : Ultrafast Shaper Recognition with CREDO Atom Types VS : Virtual Screening WHO : World Heath Organization L.monocytogenes : Listeria monocytogenes