[Frontiers in Bioscience E5, 864-882, June 1, 2013]

Hybrid-drug design targeting Pseudomonas aeruginosa DHPS and DHFR

Premkumar Jayaraman1, Kishore R Sakharkar2 , Lim Chu Sing Daniel1 , Mohammad Imran Siddiqi3, Sarinder Kaur Dhillon4, Meena K Sakharkar5

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


1. Abstract
2. Introduction
3. Methods
3.1. Ligand dataset preparation and properties prediction
3.2. Target structure preparation
3.3. Molecular docking
3.4. Molecular dynamics simulations
4. Results and discussion
4.1. Dual target design hypothesis
4.2. In silico calculations of physico-chemical, drug-likeness and toxicity risks analysis
4.3. Electronic property analysis
4.4. Homology modeling and validation of the predicted structures
4.5. Molecular docking
3.5.1. Docking of DHPPP and proposed compounds at the pterin binding site of DHPS
3.5.2. Docking of methotrexate and proposed compounds at the folate binding site of DHFR
4.6. Molecular dynamics simulations
5. Conclusion
6. Acknowledgements
7. References


In this study, we successfully present the dual-target 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 stereo-electronic 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 folate-binding 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 hybrid-drugs development.