| Autor: |
Simithy, Johayra, Fuanta, Ngolui Rene, Alturki, Mansour, Hobrath, Judith V., Wahba, Amir E., Pina, Ivett, Rath, Jnanendra, Hamann, Mark T., DeRuiter, Jack, Goodwin, Douglas C., Calderón, Angela I. |
| Zdroj: |
Biochemistry; July 2018, Vol. 57 Issue: 32 p4923-4933, 11p |
| Abstrakt: |
Tuberculosis represents a significant public health crisis. There is an urgent need for novel molecular scaffolds against this pathogen. We screened a small library of marine-derived compounds against shikimate kinase from Mycobacterium tuberculosis(MtSK), a promising target for antitubercular drug development. Six manzamines previously shown to be active against M. tuberculosiswere characterized as MtSK inhibitors: manzamine A (1), 8-hydroxymanzamine A (2), manzamine E (3), manzamine F (4), 6-deoxymanzamine X (5), and 6-cyclohexamidomanzamine A (6). All six showed mixed noncompetitive inhibition of MtSK. The lowest KIvalues were obtained for 6across all MtSK–substrate complexes. Time-dependent analyses revealed two-step, slow-binding inhibition. The behavior of 1was typical; initial formation of an enzyme–inhibitor complex (EI) obeyed an apparent KIof ∼30 μM with forward (k5) and reverse (k6) rate constants for isomerization to an EI* complex of 0.18 and 0.08 min–1, respectively. In contrast, 6showed a lower KIfor the initial encounter complex (∼1.5 μM), substantially faster isomerization to EI* (k5= 0.91 min–1), and slower back conversion of EI* to EI (k6= 0.04 min–1). Thus, the overall inhibition constants, KI*, for 1and 6were 10 and 0.06 μM, respectively. These findings were consistent with docking predictions of a favorable binding mode and a second, less tightly bound pose for 6at MtSK. Our results suggest that manzamines, in particular 6, constitute a new scaffold from which drug candidates with novel mechanisms of action could be designed for the treatment of tuberculosis by targeting MtSK. |
| Databáze: |
Supplemental Index |
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