Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is an important threat as it causes serious hospital and community acquired infections with deathly outcomes oftentimes, therefore, development of new treatments against this bacterium is a priority. Shikimate kinase, an enzyme in the shikimate pathway, is considered a good target for developing antimicrobial drugs; this is given because of its pathway, which is essential in bacteria whereas it is absent in mammals. In this work, a computer-assisted drug design strategy was used to report the first potentials inhibitors for Shikimate kinase from methicillin-resistant Staphylococcus aureus (SaSK), employing approximately 5 million compounds from ZINC15 database. Diverse filtering criteria, related to druglike characteristics and virtual docking screening in the shikimate binding site, were performed to select structurally diverse potential inhibitors from SaSK. Molecular dynamics simulations were performed to elucidate the dynamic behavior of each SaSK–ligand complex. The potential inhibitors formed important interactions with residues that are crucial for enzyme catalysis, such as Asp37, Arg61, Gly82, and Arg138. Therefore, the compounds reported provide valuable information and can be seen as the first step toward developing SaSK inhibitors in the search of new drugs against MRSA.
Highlights
Today, antimicrobial resistance in bacteria has become a serious healthcare concern [1]; the World Health Organization (WHO) published a list of 12 bacteria in 2017 [2], their level of resistance to antibiotics has become so grave, that they represent an important threat.these organisms have been declared priority pathogens to encourage antibiotic drug design by pharmaceutical companies [3]
Methicillin-resistant Staphylococcus aureus (MRSA) has been widely known as a major cause of nosocomial and community-acquired infections that range from mild cases, such as skin and soft tissue infections, to more serious and deadlier, like bacteremia, osteomyelitis, and infective endocarditis [4]
This study was initiated to work with a chemical library of around 5 million small molecules under a computer-assisted drug design strategy; it included virtual screening, ADME-Tox properties predictions, and molecular dynamics simulations; it was completed to report the first set of potential inhibitors from structural characterization of SK from MRSA (SaSK)
Summary
Antimicrobial resistance in bacteria has become a serious healthcare concern [1]; the World Health Organization (WHO) published a list of 12 bacteria in 2017 [2], their level of resistance to antibiotics has become so grave, that they represent an important threat These organisms have been declared priority pathogens to encourage antibiotic drug design by pharmaceutical companies [3]. SP links carbohydrate metabolism to aromatic compounds biosynthesis by means of seven metabolic steps culminating in chorismate production, an important precursor for the synthesis of aromatic amino acids, folate, ubiquinone, among other essential molecules [13] This route has been previously validated as an antimicrobial target [14], the design of inhibitors against enzymes of this route has gained significant attention over the years [15]. This study was initiated to work with a chemical library of around 5 million small molecules under a computer-assisted drug design strategy; it included virtual screening, ADME-Tox properties predictions, and molecular dynamics simulations; it was completed to report the first set of potential inhibitors from SaSK
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