Novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa GyrB/ParE and DHFR
Background: There is a dearth of treatment options for community-acquired and nosocomial Pseudomonas infections due to several rapidly emerging multidrug resistant phenotypes, which show resistance even to combination therapy. As an alternative, developing selective promiscuous hybrid compounds for...
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sg-ntu-dr.10356-1063102023-12-29T06:46:08Z Novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa GyrB/ParE and DHFR Jayaraman, Premkumar Lim, ChuSing Siddiqi, Mohammad Imran Sakharkar, Kishore R. Dhillon, Sarinder K. Sakharkar, Meena K. BioMedical Engineering Research Centre DRNTU::Science::Medicine::Biomedical engineering Background: There is a dearth of treatment options for community-acquired and nosocomial Pseudomonas infections due to several rapidly emerging multidrug resistant phenotypes, which show resistance even to combination therapy. As an alternative, developing selective promiscuous hybrid compounds for simultaneous modulation of multiple targets is highly appreciated because it is difficult for the pathogen to develop resistance when an inhibitor has activity against multiple targets. Methods: In line with our previous work on phytochemical–antibiotic combination assays and knowledge-based methods, using a fragment combination approach we here report a novel drug design strategy of conjugating synergistic phytochemical–antibiotic combinations into a single hybrid entity for multi-inhibition of P. aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B (ParE) and dihydrofolate reductase (DHFR) enzymes. The designed conjugates were evaluated for their multitarget specificity using various computational methods including docking and dynamic simulations, drug-likeness using molecular properties calculations, and pharmacophoric features by stereoelectronic property predictions. Results: Evaluation of the designed hybrid compounds based on their physicochemical properties has indicated that they are promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereoelectronic properties such as HOMO (highest occupied molecular orbital), LUMO (lowest unoccupied molecular orbital), and MEP (molecular electrostatic potential) maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for multitarget inhibition. Furthermore, docking and dynamics simulations revealed that the designed compounds have favorable binding affinity and stability in both the ATP-binding sites of GyrB/ParE and the folate-binding site of DHFR, by forming strong hydrogen bonds and hydrophobic interactions with key active site residues. Conclusion: This new design concept of hybrid “phyto-drug” scaffolds, and their simultaneous perturbation of well-established antibacterial targets from two unrelated pathways, appears to be very promising and could serve as a prospective lead in multitarget drug discovery. Published version 2014-10-10T08:26:57Z 2019-12-06T22:08:50Z 2014-10-10T08:26:57Z 2019-12-06T22:08:50Z 2013 2013 Journal Article Jayaraman, P., Sakharkar, K. R., Lim, C., Siddiqi, M. I., Dhillon, S. K., & Sakharkar, M. K. (2013). Novel phytochemical antibiotic conjugates as multitarget inhibitors of Pseudomononas aeruginosa GyrB/ParE and DHFR. Drug design, development and therapy, 7, 449-475. 1177-8881 https://hdl.handle.net/10356/106310 http://hdl.handle.net/10220/23996 10.2147/DDDT.S43964 23818757 en Drug design, development and therapy © 2013 Jayaraman et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. 27 p. application/pdf |
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DRNTU::Science::Medicine::Biomedical engineering Jayaraman, Premkumar Lim, ChuSing Siddiqi, Mohammad Imran Sakharkar, Kishore R. Dhillon, Sarinder K. Sakharkar, Meena K. Novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa GyrB/ParE and DHFR |
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Background: There is a dearth of treatment options for community-acquired and nosocomial Pseudomonas infections due to several rapidly emerging multidrug resistant phenotypes, which show resistance even to combination therapy. As an alternative, developing selective promiscuous hybrid compounds for simultaneous modulation of multiple targets is highly appreciated because it is difficult for the pathogen to develop resistance when an inhibitor has activity against multiple targets.
Methods: In line with our previous work on phytochemical–antibiotic combination assays and knowledge-based methods, using a fragment combination approach we here report a novel drug design strategy of conjugating synergistic phytochemical–antibiotic combinations into a single hybrid entity for multi-inhibition of P. aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B (ParE) and dihydrofolate reductase (DHFR) enzymes. The designed conjugates were evaluated for their multitarget specificity using various computational methods including docking and dynamic simulations, drug-likeness using molecular properties calculations, and pharmacophoric features by stereoelectronic property predictions.
Results: Evaluation of the designed hybrid compounds based on their physicochemical properties has indicated that they are promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereoelectronic properties such as HOMO (highest occupied molecular orbital), LUMO (lowest unoccupied molecular orbital), and MEP (molecular electrostatic potential) maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for multitarget inhibition. Furthermore, docking and dynamics simulations revealed that the designed compounds have favorable binding affinity and stability in both the ATP-binding sites of GyrB/ParE and the folate-binding site of DHFR, by forming strong hydrogen bonds and hydrophobic interactions with key active site residues.
Conclusion: This new design concept of hybrid “phyto-drug” scaffolds, and their simultaneous perturbation of well-established antibacterial targets from two unrelated pathways, appears to be very promising and could serve as a prospective lead in multitarget drug discovery. |
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BioMedical Engineering Research Centre |
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BioMedical Engineering Research Centre Jayaraman, Premkumar Lim, ChuSing Siddiqi, Mohammad Imran Sakharkar, Kishore R. Dhillon, Sarinder K. Sakharkar, Meena K. |
format |
Article |
author |
Jayaraman, Premkumar Lim, ChuSing Siddiqi, Mohammad Imran Sakharkar, Kishore R. Dhillon, Sarinder K. Sakharkar, Meena K. |
author_sort |
Jayaraman, Premkumar |
title |
Novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa GyrB/ParE and DHFR |
title_short |
Novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa GyrB/ParE and DHFR |
title_full |
Novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa GyrB/ParE and DHFR |
title_fullStr |
Novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa GyrB/ParE and DHFR |
title_full_unstemmed |
Novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa GyrB/ParE and DHFR |
title_sort |
novel phytochemical antibiotic conjugates as multitarget inhibitors of pseudomononas aeruginosa gyrb/pare and dhfr |
publishDate |
2014 |
url |
https://hdl.handle.net/10356/106310 http://hdl.handle.net/10220/23996 |
_version_ |
1787136438821715968 |