IMR Press / FBE / Volume 5 / Issue 3 / DOI: 10.2741/E666

Frontiers in Bioscience-Elite (FBE) is published by IMR Press from Volume 13 Issue 2 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.


Hybrid-drug design targeting Pseudomonas aeruginosa DHPS and DHFR

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1 Biomedical Engineering Research Centre, Nanyang Technological University, Singapore
2 OmicsVista, Singapore
3 Molecular and Structural Biology Division, Central Drug Research Institute, India
4 Institute of Biological Sciences, Faculty of Science, University Malaya, Kuala Lumpur, Malaysia
5 School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan

*Author to whom correspondence should be addressed.

Front. Biosci. (Elite Ed) 2013, 5(3), 864–882;
Published: 1 June 2013

In this study, we successfully present the dualtarget design hypothesis to inhibit both dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) enzymes using a novel scheme that integrates our previous antibiotic-phytochemical interaction data, fragment combination and knowledge-based methods. Both the enzymes are well established antibacterial targets from folate biosynthesis pathway and their synergistic modulation by a single hybrid entity may have profound therapeutic benefits. Evaluation of the designed hybrid compounds based on their physico-chemical properties has indicated them as promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereoelectronic properties such as HOMO, LUMO and MEP maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for dual-site interactions. Furthermore, docking and dynamics simulation studies reveal that the designed hybrid compounds have favorable binding affinity and stability in both pterin-binding site of DHPS and folatebinding site of DHFR by forming strong hydrogen bonds and hydrophobic interactions with key active-site residues. Looking forward this study could serve as a prospective lead in the process of new natural-product based hybriddrugs development.

Hybrid-drug Design
Multi-Target Inhibitors
Drug Resistance
Dihydrofolate Reductase
Dihydropteroate Synthase
Dual Action Compounds
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