Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation
The lack of success in target-based screening approaches to the discovery of antibacterial agents has led to reemergence of phenotypic screening as a successful approach of identifying bioactive, antibacterial compounds. A challenge though with this route is then to identify the molecular target(s)...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science
2022
|
| Subjects: | |
| Online Access: | https://doi.org/10.1371/journal.pone.0121492 http://hdl.handle.net/11408/4895 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1779905282951872512 |
|---|---|
| author | Mugumbate, Grace Abrahams, Katherine A. Cox, Jonathan A. G. Papadatos, George Westen, Gerard van Lelièvre, Joël Calus, Szymon T. Loman, Nicholas J. Ballell, Lluis Barros, David Overington, John P. Besra, Gurdyal S. |
| author_facet | Mugumbate, Grace Abrahams, Katherine A. Cox, Jonathan A. G. Papadatos, George Westen, Gerard van Lelièvre, Joël Calus, Szymon T. Loman, Nicholas J. Ballell, Lluis Barros, David Overington, John P. Besra, Gurdyal S. |
| author_sort | Mugumbate, Grace |
| collection | DSpace |
| description | The lack of success in target-based screening approaches to the discovery of antibacterial agents has led to reemergence of phenotypic screening as a successful approach of identifying bioactive, antibacterial compounds. A challenge though with this route is then to identify the molecular target(s) and mechanism of action of the hits. This target identification, or deorphanization step, is often essential in further optimization and validation studies. Direct experimental identification of the molecular target of a screening hit is often complex, precisely because the properties and specificity of the hit are not yet optimized against that target, and so many false positives are often obtained. An alternative is to use computational, predictive, approaches to hypothesize a mechanism of action, which can then be validated in a more directed and efficient manner. Specifically here we present experimental validation of an in silico prediction from a large-scale screen performed against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. The two potent anti-tubercular compounds studied in this case, belonging to the tetrahydro-1,3,5-triazin-2-amine (THT) family, were predicted and confirmed to be an inhibitor of dihydrofolate reductase (DHFR), a known essential Mtb gene, and already clinically validated as a drug target. Given the large number of similar screening data sets shared amongst the community, this in vitro validation of these target predictions gives weight to computational approaches to establish the mechanism of action (MoA) of novel screening hit. |
| format | Article |
| id | ir-11408-4895 |
| institution | My University |
| language | English |
| publishDate | 2022 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | ir-11408-48952022-06-28T07:43:11Z Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation Mugumbate, Grace Abrahams, Katherine A. Cox, Jonathan A. G. Papadatos, George Westen, Gerard van Lelièvre, Joël Calus, Szymon T. Loman, Nicholas J. Ballell, Lluis Barros, David Overington, John P. Besra, Gurdyal S. Mycobacterium tuberculosis Mycobacterium bovis Tuberculosis drug discovery Drug interactions Crystal structure The lack of success in target-based screening approaches to the discovery of antibacterial agents has led to reemergence of phenotypic screening as a successful approach of identifying bioactive, antibacterial compounds. A challenge though with this route is then to identify the molecular target(s) and mechanism of action of the hits. This target identification, or deorphanization step, is often essential in further optimization and validation studies. Direct experimental identification of the molecular target of a screening hit is often complex, precisely because the properties and specificity of the hit are not yet optimized against that target, and so many false positives are often obtained. An alternative is to use computational, predictive, approaches to hypothesize a mechanism of action, which can then be validated in a more directed and efficient manner. Specifically here we present experimental validation of an in silico prediction from a large-scale screen performed against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. The two potent anti-tubercular compounds studied in this case, belonging to the tetrahydro-1,3,5-triazin-2-amine (THT) family, were predicted and confirmed to be an inhibitor of dihydrofolate reductase (DHFR), a known essential Mtb gene, and already clinically validated as a drug target. Given the large number of similar screening data sets shared amongst the community, this in vitro validation of these target predictions gives weight to computational approaches to establish the mechanism of action (MoA) of novel screening hit. 2022-06-28T07:43:10Z 2022-06-28T07:43:10Z 2015 Article Mugumbate G, Abrahams KA, Cox JAG, Papadatos G, van Westen G, Lelièvre J, et al. (2015) Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation. PLoS ONE 10(3): e0121492. https://doi.org/10.1371/journal.pone.0121492 1932-6203 https://doi.org/10.1371/journal.pone.0121492 http://hdl.handle.net/11408/4895 en PLoS ONE;10(3) open Public Library of Science |
| spellingShingle | Mycobacterium tuberculosis Mycobacterium bovis Tuberculosis drug discovery Drug interactions Crystal structure Mugumbate, Grace Abrahams, Katherine A. Cox, Jonathan A. G. Papadatos, George Westen, Gerard van Lelièvre, Joël Calus, Szymon T. Loman, Nicholas J. Ballell, Lluis Barros, David Overington, John P. Besra, Gurdyal S. Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation |
| title | Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation |
| title_full | Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation |
| title_fullStr | Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation |
| title_full_unstemmed | Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation |
| title_short | Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation |
| title_sort | mycobacterial dihydrofolate reductase inhibitors identified using chemogenomic methods and in vitro validation |
| topic | Mycobacterium tuberculosis Mycobacterium bovis Tuberculosis drug discovery Drug interactions Crystal structure |
| url | https://doi.org/10.1371/journal.pone.0121492 http://hdl.handle.net/11408/4895 |
| work_keys_str_mv | AT mugumbategrace mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT abrahamskatherinea mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT coxjonathanag mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT papadatosgeorge mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT westengerardvan mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT lelievrejoel mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT calusszymont mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT lomannicholasj mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT ballelllluis mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT barrosdavid mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT overingtonjohnp mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation AT besragurdyals mycobacterialdihydrofolatereductaseinhibitorsidentifiedusingchemogenomicmethodsandinvitrovalidation |