The inhibitory and binding studies of methyl-sulfone hydroxamate based inhibitors against LpxC from drug resistant Moraxella catarrhalis using biophysical, biochemical and in silico approaches.
Int J Biol Macromol
; 118(Pt B): 1747-1762, 2018 Oct 15.
Article
en En
| MEDLINE
| ID: mdl-30017978
ABSTRACT
Several reported potential compounds against UDP-3-O-(R-3-Hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) have shown large variation in the potency and efficacy. The differential susceptibility and selective binding of these inhibitors against LpxC are still unexplored. In the present work, we have characterized LpxC from Moraxella catarrhalis (McLpxC) and investigated its binding with potent inhibitors LpxC-2 and LpxC-4 using biochemical, biophysical and in silico approaches. The circular dichroism studies have revealed the changes in the secondary and tertiary structure of McLpxC upon inhibitors binding. The fluorescence quenching mechanism was found to be static with kqâ¯>â¯1010 suggesting the ground state complex formation between the McLpxC and inhibitors. Altogether spectroscopic findings suggest that the interaction of LpxC-4 and LpxC-2 caused conformational changes marked by the loss of α-helical content in McLpxC. In ITC based studies, both inhibitors have shown comparable binding affinities (KDâ¯=â¯~10.0⯵Μ), and their interactions were exothermically driven by enthalpy change. The docking studies have shown the possibility of two binding sites in McLpxC for these inhibitors with similar binding energies (~10.0â¯kcalâ¯mol-1). Thus, the present study significantly suggests that further optimization and utilization of molecules based on this scaffold will be helpful in designing the new antimicrobial agents targeting LpxC.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfonas
/
Dimetilsulfóxido
/
Moraxella catarrhalis
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Amidohidrolasas
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Ácidos Hidroxámicos
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Antibacterianos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Int J Biol Macromol
Año:
2018
Tipo del documento:
Article
País de afiliación:
India