Identification of Novel Antimicrobial Compounds Targeting <i>Mycobacterium tuberculosis S</i>-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening
The emergence of multidrug-resistant and extensively drug-resistant <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) has become a major medical problem. <i>S</i>-adenosyl-L-homocysteine hydrolase (MtSAHH) was selected as the target protein for the identi...
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| Format: | Article |
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MDPI AG
2024-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/6/1303 |
| _version_ | 1797239892414038016 |
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| author | Hazuki Ito Kohei Monobe Saya Okubo Shunsuke Aoki |
| author_facet | Hazuki Ito Kohei Monobe Saya Okubo Shunsuke Aoki |
| author_sort | Hazuki Ito |
| collection | DOAJ |
| description | The emergence of multidrug-resistant and extensively drug-resistant <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) has become a major medical problem. <i>S</i>-adenosyl-L-homocysteine hydrolase (MtSAHH) was selected as the target protein for the identification of novel anti-TB drugs. Dual hierarchical in silico Structure-Based Drug Screening was performed using a 3D compound structure library (with over 150 thousand synthetic chemicals) to identify compounds that bind to MtSAHH’s active site. In vitro experiments were conducted to verify whether the nine compounds selected as new drug candidates exhibited growth-inhibitory effects against mycobacteria. Eight of the nine compounds that were predicted by dual hierarchical screening showed growth-inhibitory effects against <i>Mycobacterium smegmatis</i> (<i>M. smegmatis</i>), a model organism for <i>M. tuberculosis</i>. Compound <b>7</b> showed the strongest antibacterial activity, with an IC<sub>50</sub> value of 30.2 µM. Compound <b>7</b> did not inhibit the growth of Gram-negative bacteria or exert toxic effects on human cells. Molecular dynamics simulations of 40 ns using the MtSAHH–Compound <b>7</b> complex structure suggested that Compound <b>7</b> interacts stably with the MtSAHH active site. These in silico and in vitro results suggested that Compound <b>7</b> is a promising lead compound for the development of new anti-TB drugs. |
| first_indexed | 2024-04-24T17:58:45Z |
| format | Article |
| id | doaj.art-d9bd6815b3b34ac893554500334c78c6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-24T17:58:45Z |
| publishDate | 2024-03-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-d9bd6815b3b34ac893554500334c78c62024-03-27T13:56:59ZengMDPI AGMolecules1420-30492024-03-01296130310.3390/molecules29061303Identification of Novel Antimicrobial Compounds Targeting <i>Mycobacterium tuberculosis S</i>-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug ScreeningHazuki Ito0Kohei Monobe1Saya Okubo2Shunsuke Aoki3Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanDepartment of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka 820-8502, JapanThe emergence of multidrug-resistant and extensively drug-resistant <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) has become a major medical problem. <i>S</i>-adenosyl-L-homocysteine hydrolase (MtSAHH) was selected as the target protein for the identification of novel anti-TB drugs. Dual hierarchical in silico Structure-Based Drug Screening was performed using a 3D compound structure library (with over 150 thousand synthetic chemicals) to identify compounds that bind to MtSAHH’s active site. In vitro experiments were conducted to verify whether the nine compounds selected as new drug candidates exhibited growth-inhibitory effects against mycobacteria. Eight of the nine compounds that were predicted by dual hierarchical screening showed growth-inhibitory effects against <i>Mycobacterium smegmatis</i> (<i>M. smegmatis</i>), a model organism for <i>M. tuberculosis</i>. Compound <b>7</b> showed the strongest antibacterial activity, with an IC<sub>50</sub> value of 30.2 µM. Compound <b>7</b> did not inhibit the growth of Gram-negative bacteria or exert toxic effects on human cells. Molecular dynamics simulations of 40 ns using the MtSAHH–Compound <b>7</b> complex structure suggested that Compound <b>7</b> interacts stably with the MtSAHH active site. These in silico and in vitro results suggested that Compound <b>7</b> is a promising lead compound for the development of new anti-TB drugs.https://www.mdpi.com/1420-3049/29/6/1303tuberculosis<i>Mycobacterium</i><i>Mycobacterium tuberculosis S</i>-adenosyl-L-homocysteine hydrolase (MtSAHH)in silico structure-based drug screening (SBDS)docking simulationmolecular dynamics simulation |
| spellingShingle | Hazuki Ito Kohei Monobe Saya Okubo Shunsuke Aoki Identification of Novel Antimicrobial Compounds Targeting <i>Mycobacterium tuberculosis S</i>-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening Molecules tuberculosis <i>Mycobacterium</i> <i>Mycobacterium tuberculosis S</i>-adenosyl-L-homocysteine hydrolase (MtSAHH) in silico structure-based drug screening (SBDS) docking simulation molecular dynamics simulation |
| title | Identification of Novel Antimicrobial Compounds Targeting <i>Mycobacterium tuberculosis S</i>-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening |
| title_full | Identification of Novel Antimicrobial Compounds Targeting <i>Mycobacterium tuberculosis S</i>-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening |
| title_fullStr | Identification of Novel Antimicrobial Compounds Targeting <i>Mycobacterium tuberculosis S</i>-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening |
| title_full_unstemmed | Identification of Novel Antimicrobial Compounds Targeting <i>Mycobacterium tuberculosis S</i>-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening |
| title_short | Identification of Novel Antimicrobial Compounds Targeting <i>Mycobacterium tuberculosis S</i>-Adenosyl-L-Homocysteine Hydrolase Using Dual Hierarchical In Silico Structure-Based Drug Screening |
| title_sort | identification of novel antimicrobial compounds targeting i mycobacterium tuberculosis s i adenosyl l homocysteine hydrolase using dual hierarchical in silico structure based drug screening |
| topic | tuberculosis <i>Mycobacterium</i> <i>Mycobacterium tuberculosis S</i>-adenosyl-L-homocysteine hydrolase (MtSAHH) in silico structure-based drug screening (SBDS) docking simulation molecular dynamics simulation |
| url | https://www.mdpi.com/1420-3049/29/6/1303 |
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