Molecules 2014, 19(4), 4491-4509; doi:10.3390/molecules19044491
Article

Inhibition and Biochemical Characterization of Methicillin-Resistant Staphylococcus aureus Shikimate Dehydrogenase: An in Silico and Kinetic Study

1, 2,* email, 3, 4, 4, 1 and 1,* email
Received: 6 February 2014; in revised form: 3 April 2014 / Accepted: 4 April 2014 / Published: 10 April 2014
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: Methicillin-resistant Staphylococcus auerus (MRSA) strains are having a major impact worldwide, and due to their resistance to all β-lactams, an urgent need for new drugs is emerging. In this regard, the shikimate pathway is considered to be one of the metabolic features of bacteria and is absent in humans. Therefore enzymes involved in this route, such as shikimate dehydrogenase (SDH), are considered excellent targets for discovery of novel antibacterial drugs. In this study, the SDH from MRSA (SaSDH) was characterized. The results showed that the enzyme is a monomer with a molecular weight of 29 kDa, an optimum temperature of 65 °C, and a maximal pH range of 9–11 for its activity. Kinetic studies revealed that SDH showed Michaelis-Menten kinetics toward both substrates (shikimate and NADP+). Initial velocity analysis suggested that SaSDH catalysis followed a sequential random mechanism. Additionally, a tridimensional model of SaSDH was obtained by homology modeling and validated. Through virtual screening three inhibitors of SaSDH were found (compounds 238, 766 and 894) and their inhibition constants and mechanism were obtained. Flexible docking studies revealed that these molecules make interactions with catalytic residues. The data of this study could serve as starting point in the search of new chemotherapeutic agents against MRSA.
Keywords: MRSA; shikimate dehydrogenase; homology modeling; virtual screening; flexible docking; enzyme kinetics
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MDPI and ACS Style

Avitia-Domínguez, C.; Sierra-Campos, E.; Salas-Pacheco, J.M.; Nájera, H.; Rojo-Domínguez, A.; Cisneros-Martínez, J.; Téllez-Valencia, A. Inhibition and Biochemical Characterization of Methicillin-Resistant Staphylococcus aureus Shikimate Dehydrogenase: An in Silico and Kinetic Study. Molecules 2014, 19, 4491-4509.

AMA Style

Avitia-Domínguez C, Sierra-Campos E, Salas-Pacheco JM, Nájera H, Rojo-Domínguez A, Cisneros-Martínez J, Téllez-Valencia A. Inhibition and Biochemical Characterization of Methicillin-Resistant Staphylococcus aureus Shikimate Dehydrogenase: An in Silico and Kinetic Study. Molecules. 2014; 19(4):4491-4509.

Chicago/Turabian Style

Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Salas-Pacheco, José M.; Nájera, Hugo; Rojo-Domínguez, Arturo; Cisneros-Martínez, Jorge; Téllez-Valencia, Alfredo. 2014. "Inhibition and Biochemical Characterization of Methicillin-Resistant Staphylococcus aureus Shikimate Dehydrogenase: An in Silico and Kinetic Study." Molecules 19, no. 4: 4491-4509.

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