title: Hybrid-drug design targeting Pseudomonas aeruginosa dihydropteroate synthase and dihydrofolate reductase
abstract: 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.
authors.affiliation: Biomedical Engineering Research Centre, Nanyang Technological University, Singapore.
authors.forename: Premkumar
authors.initials: P
authors.lastname: Jayaraman
authors.forename: Kishore R
authors.initials: KR
authors.lastname: Sakharkar
authors.forename: Lim Chu Sing
authors.initials: LC
authors.lastname: Daniel
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.forename: Sarinder Kaur
authors.initials: SK
authors.lastname: Dhillon
authors.forename: Meena K
authors.initials: MK
authors.lastname: Sakharkar
mesh_terms: D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase