Identification of potential inhibitors of Mycobacterium tuberculosis shikimate kinase : molecular docking, in silico toxicity and in vitro experiments
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG..
Tuberculosis (TB) is one of the main causes of death from a single pathological agent, Mycobacterium tuberculosis (Mtb). In addition, the emergence of drug-resistant TB strains has exacerbated even further the treatment outcome of TB patients. It is thus needed the search for new therapeutic strategies to improve the current treatment and to circumvent the resistance mechanisms of Mtb. The shikimate kinase (SK) is the fifth enzyme of the shikimate pathway, which is essential for the survival of Mtb. The shikimate pathway is absent in humans, thereby indicating SK as an attractive target for the development of anti-TB drugs. In this work, a combination of in silico and in vitro techniques was used to identify potential inhibitors for SK from Mtb (MtSK). All compounds of our in-house database (Centro de Pesquisas em Biologia Molecular e Funcional, CPBMF) were submitted to in silico toxicity analysis to evaluate the risk of hepatotoxicity. Docking experiments were performed to identify the potential inhibitors of MtSK according to the predicted binding energy. In vitro inhibitory activity of MtSK-catalyzed chemical reaction at a single compound concentration was assessed. Minimum inhibitory concentration values for in vitro growth of pan-sensitive Mtb H37Rv strain were also determined. The mixed approach implemented in this work was able to identify five compounds that inhibit both MtSK and the in vitro growth of Mtb.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:37 |
|---|---|
| Enthalten in: |
Journal of computer-aided molecular design - 37(2023), 3 vom: 22. März, Seite 117-128 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Freitas de Freitas, Talita [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antitubercular Agents |
|---|
| Anmerkungen: |
Date Completed 09.03.2023 Date Revised 03.04.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s10822-022-00495-w |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM350592950 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM350592950 | ||
| 003 | DE-627 | ||
| 005 | 20231226045339.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s10822-022-00495-w |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1168.xml |
| 035 | |a (DE-627)NLM350592950 | ||
| 035 | |a (NLM)36547753 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Freitas de Freitas, Talita |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Identification of potential inhibitors of Mycobacterium tuberculosis shikimate kinase |b molecular docking, in silico toxicity and in vitro experiments |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 09.03.2023 | ||
| 500 | |a Date Revised 03.04.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG. | ||
| 520 | |a Tuberculosis (TB) is one of the main causes of death from a single pathological agent, Mycobacterium tuberculosis (Mtb). In addition, the emergence of drug-resistant TB strains has exacerbated even further the treatment outcome of TB patients. It is thus needed the search for new therapeutic strategies to improve the current treatment and to circumvent the resistance mechanisms of Mtb. The shikimate kinase (SK) is the fifth enzyme of the shikimate pathway, which is essential for the survival of Mtb. The shikimate pathway is absent in humans, thereby indicating SK as an attractive target for the development of anti-TB drugs. In this work, a combination of in silico and in vitro techniques was used to identify potential inhibitors for SK from Mtb (MtSK). All compounds of our in-house database (Centro de Pesquisas em Biologia Molecular e Funcional, CPBMF) were submitted to in silico toxicity analysis to evaluate the risk of hepatotoxicity. Docking experiments were performed to identify the potential inhibitors of MtSK according to the predicted binding energy. In vitro inhibitory activity of MtSK-catalyzed chemical reaction at a single compound concentration was assessed. Minimum inhibitory concentration values for in vitro growth of pan-sensitive Mtb H37Rv strain were also determined. The mixed approach implemented in this work was able to identify five compounds that inhibit both MtSK and the in vitro growth of Mtb | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a AutoDock Vina | |
| 650 | 4 | |a Docking | |
| 650 | 4 | |a Mycobacterium tuberculosis | |
| 650 | 4 | |a PyRx | |
| 650 | 4 | |a Shikimate kinase | |
| 650 | 4 | |a pkCSM | |
| 650 | 7 | |a shikimate |2 NLM | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 700 | 1 | |a Roth, Candida Deves |e verfasserin |4 aut | |
| 700 | 1 | |a Abbadi, Bruno Lopes |e verfasserin |4 aut | |
| 700 | 1 | |a Hopf, Fernanda Souza Macchi |e verfasserin |4 aut | |
| 700 | 1 | |a Perelló, Marcia Alberton |e verfasserin |4 aut | |
| 700 | 1 | |a de Matos Czeczot, Alexia |e verfasserin |4 aut | |
| 700 | 1 | |a de Souza, Eduardo Vieira |e verfasserin |4 aut | |
| 700 | 1 | |a Borsoi, Ana Flávia |e verfasserin |4 aut | |
| 700 | 1 | |a Machado, Pablo |e verfasserin |4 aut | |
| 700 | 1 | |a Bizarro, Cristiano Valim |e verfasserin |4 aut | |
| 700 | 1 | |a Basso, Luiz Augusto |e verfasserin |4 aut | |
| 700 | 1 | |a Timmers, Luis Fernando Saraiva Macedo |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of computer-aided molecular design |d 1995 |g 37(2023), 3 vom: 22. März, Seite 117-128 |w (DE-627)NLM012724300 |x 1573-4951 |7 nnns |
| 773 | 1 | 8 | |g volume:37 |g year:2023 |g number:3 |g day:22 |g month:03 |g pages:117-128 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s10822-022-00495-w |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 37 |j 2023 |e 3 |b 22 |c 03 |h 117-128 | ||