Finding the First Potential Inhibitors of Shikimate Kinase from Methicillin Resistant Staphylococcus aureus through Computer-Assisted Drug Design

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.

Functional Analysis of Hypothetical Proteins of Vibrio parahaemolyticus Reveals the Presence of Virulence Factors and Growth-Related Enzymes With Therapeutic Potential

“…Studies are currently being conducted with the goal of identifying shikimate kinase inhibitors that are effective against methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis . 84 - 86 The phosphoribosyl-ATP pyrophosphohydrolase (MSR16_hyp_1190), an enzyme that is involved in the histidine biosynthesis pathway, is another possible therapeutic target. 87 It has been experimentally validated that extracts from tropical plants have the ability to block aminoacyl-tRNA hydrolase (MSR16_hyp_1287 and MSR17_hyp_580), an enzyme that is essential to the process of protein biosynthesis.…”

Unlocking Herbal Potentials: Novel Shikimate Kinase Inhibitors in the Fight Against Antibiotic Resistance

“…In addition to the inhibition of chorismate production, Shikimate Kinase inhibition causes Shikimate Acid buildup, which is fatal to many bacteria (including those mentioned previously) [24, 25]. The importance of Shikimate Kinase inhibition has been studied by many through the design and synthesis of artificial drugs through crystallization projects [4, 13, 14, 15, 28, 29, 30].…”

“…Traditionally, antibiotics, predominantly derived from fungal sources, employ a limited set of mechanisms to inhibit bacterial growth [6, 16]. Shikimate Kinase has emerged as a promising antibacterial target due to its exclusivity to bacteria and the lethality of its inhibition [4, 13, 14, 15, 28, 29, 30]. Although synthetic inhibitors have been developed, the exploration of plant-derived alternatives remains untapped.…”