Presentation Title

Synthesis and Molecular Modeling Studies of Novel Nucleoside Analogs as Inhibitors for Class B Metallo-β-Lactamase

Faculty Mentor

Ahmed Awad

Start Date

17-11-2018 8:30 AM

End Date

17-11-2018 10:30 AM

Location

CREVELING 109

Session

POSTER 1

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

Metallo-β-lactamases (MBLs) are bacterial enzymes characterized by their dizinc active site’s ability to hydrolyze clinically available β-lactam antibiotics. Herein we investigate novel nucleoside analogues for inhibition of MBLs. ICM molsoft, an in-silico molecular modeling software which implements the Monte Carlo optimization algorithm was used to predict the binding affinity, while admetSAR and swissADME search engines screened for toxicity of the proposed analogues. From computer analysis, inhibition activity was enhanced through the addition of 2-(2-aminoethoxy)ethanol linker at the 3’ position of the nucleoside sugar. The uridine analogue showed lowest toxicity and highest MBL inhibition, and was chosen along with other candidates for chemical synthesis. A synthetic pathway was conducted starting from commercially available nucleosides which were modified through oxidation of the 3’-hydroxyl on the ribose sugar, followed by an imine formation with 2-(2-aminoethoxy)ethanol and finalized by enantioselective reduction of the imine on the ribose sugar. In future work, the synthesized compounds will be tested using enzyme inhibition assays and results will be compared to those obtained by the in-silico studies.

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Nov 17th, 8:30 AM Nov 17th, 10:30 AM

Synthesis and Molecular Modeling Studies of Novel Nucleoside Analogs as Inhibitors for Class B Metallo-β-Lactamase

CREVELING 109

Metallo-β-lactamases (MBLs) are bacterial enzymes characterized by their dizinc active site’s ability to hydrolyze clinically available β-lactam antibiotics. Herein we investigate novel nucleoside analogues for inhibition of MBLs. ICM molsoft, an in-silico molecular modeling software which implements the Monte Carlo optimization algorithm was used to predict the binding affinity, while admetSAR and swissADME search engines screened for toxicity of the proposed analogues. From computer analysis, inhibition activity was enhanced through the addition of 2-(2-aminoethoxy)ethanol linker at the 3’ position of the nucleoside sugar. The uridine analogue showed lowest toxicity and highest MBL inhibition, and was chosen along with other candidates for chemical synthesis. A synthetic pathway was conducted starting from commercially available nucleosides which were modified through oxidation of the 3’-hydroxyl on the ribose sugar, followed by an imine formation with 2-(2-aminoethoxy)ethanol and finalized by enantioselective reduction of the imine on the ribose sugar. In future work, the synthesized compounds will be tested using enzyme inhibition assays and results will be compared to those obtained by the in-silico studies.