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dc.contributor.authorArooj, Mahreen
dc.contributor.authorSakkiah, Sugunadevi
dc.contributor.authorPing Cao, Guang
dc.contributor.authorWoo Lee, Keun
dc.date.accessioned2017-01-30T10:47:05Z
dc.date.available2017-01-30T10:47:05Z
dc.date.created2014-03-10T20:00:41Z
dc.date.issued2013
dc.date.submitted2014-04-10
dc.identifier.citationArooj, Mahreen and Sakkiah, Sugunadevi and Ping Cao, Guang and Woo Lee, Keun. 2013. An Innovative Strategy for Dual Inhibitor Design and Its Application in Dual Inhibition of Human Thymidylate Synthase and Dihydrofolate Reductase Enzymes. PLoS ONE. 8 (4): e60470.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/5567
dc.identifier.doi10.1371/journal.pone.0060470
dc.description.abstract

Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases. Nevertheless, to design multitarget inhibitors is concurrently a great challenge for medicinal chemists. We have developed a novel computational approach by integrating the affinity predictions from structure-based virtual screening with dual ligand-based pharmacophore to discover potential dual inhibitors of human Thymidylate synthase (hTS) and human dihydrofolate reductase (hDHFR). These are the key enzymes in folate metabolic pathway that is necessary for the biosynthesis of RNA,DNA, and protein. Their inhibition has found clinical utility as antitumor, antimicrobial, and antiprotozoal agents. A druglike database was utilized to perform dual-target docking studies. Hits identified through docking experiments were mapped over a dual pharmacophore which was developed from experimentally known dual inhibitors of hTS and hDHFR. Pharmacophore mapping procedure helped us in eliminating the compounds which do not possess basic chemical features necessary for dual inhibition. Finally, three structurally diverse hit compounds that showed key interactions at both activesites, mapped well upon the dual pharmacophore, and exhibited lowest binding energies were regarded as possible dual inhibitors of hTS and hDHFR. Furthermore, optimization studies were performed for final dual hit compound and eight optimized dual hits demonstrating excellent binding features at target systems were also regarded as possible dual inhibitors of hTS and hDHFR. In general, the strategy used in the current study could be a promising computational approach and may be generally applicable to other dual target drug designs.

dc.publisherPublic Library of Science
dc.titleAn Innovative Strategy for Dual Inhibitor Design and Its Application in Dual Inhibition of Human Thymidylate Synthase and Dihydrofolate Reductase Enzymes
dc.typeJournal Article
dcterms.dateSubmitted2014-03-11
dcterms.source.volume8
dcterms.source.number4
dcterms.source.startPage1
dcterms.source.endPage15
dcterms.source.issn19326203
dcterms.source.titlePLoS ONE
curtin.digitool.pid196148
curtin.note

This article is published under the Open Access publishing model and distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/ Please refer to the licence to obtain terms for any further reuse or distribution of this work.

curtin.pubStatusPublished
curtin.department
curtin.identifier.scriptidPUB-HEA-SBS-JT-79326
curtin.accessStatusOpen access


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