Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches
Targeting enzymes that play a role in the biosynthesis of the bacterial cell wall has long been a strategy for antibacterial discovery. In particular, the cell wall of <i>Mycobacterium tuberculosis</i> (Mtb) is a complex of three layers, one of which is Peptidoglycan, an essential compon...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/9/2805 |
| _version_ | 1797503696525852672 |
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| author | Manvi Singh Priya Kempanna Kavitha Bharatham |
| author_facet | Manvi Singh Priya Kempanna Kavitha Bharatham |
| author_sort | Manvi Singh |
| collection | DOAJ |
| description | Targeting enzymes that play a role in the biosynthesis of the bacterial cell wall has long been a strategy for antibacterial discovery. In particular, the cell wall of <i>Mycobacterium tuberculosis</i> (Mtb) is a complex of three layers, one of which is Peptidoglycan, an essential component providing rigidity and strength. UDP-GlcNAc, a precursor for the synthesis of peptidoglycan, is formed by GlmU, a bi-functional enzyme. Inhibiting GlmU Uridyltransferase activity has been proven to be an effective anti-bacterial, but its similarity with human enzymes has been a deterrent to drug development. To develop Mtb selective hits, the Mtb GlmU substrate binding pocket was compared with structurally similar human enzymes to identify selectivity determining factors. Substrate binding pockets and conformational changes upon substrate binding were analyzed and MD simulations with substrates were performed to quantify crucial interactions to develop critical pharmacophore features. Thereafter, two strategies were applied to propose potent and selective bacterial GlmU Uridyltransferase domain inhibitors: (i) optimization of existing inhibitors, and (ii) identification by virtual screening. The binding modes of hits identified from virtual screening and ligand growing approaches were evaluated further for their ability to retain stable contacts within the pocket during 20 ns MD simulations. Hits that are predicted to be more potent than existing inhibitors and selective against human homologues could be of great interest for rejuvenating drug discovery efforts towards targeting the Mtb cell wall for antibacterial discovery. |
| first_indexed | 2024-03-10T03:54:23Z |
| format | Article |
| id | doaj.art-28374e2f6f1a4d6a8d4a179d51b5585a |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:54:23Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-28374e2f6f1a4d6a8d4a179d51b5585a2023-11-23T08:49:54ZengMDPI AGMolecules1420-30492022-04-01279280510.3390/molecules27092805Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design ApproachesManvi Singh0Priya Kempanna1Kavitha Bharatham2Center for Chemical Biology & Therapeutics, InStem, Bellary Road, Bangalore, Karnataka 560065, IndiaCenter for Chemical Biology & Therapeutics, InStem, Bellary Road, Bangalore, Karnataka 560065, IndiaCenter for Chemical Biology & Therapeutics, InStem, Bellary Road, Bangalore, Karnataka 560065, IndiaTargeting enzymes that play a role in the biosynthesis of the bacterial cell wall has long been a strategy for antibacterial discovery. In particular, the cell wall of <i>Mycobacterium tuberculosis</i> (Mtb) is a complex of three layers, one of which is Peptidoglycan, an essential component providing rigidity and strength. UDP-GlcNAc, a precursor for the synthesis of peptidoglycan, is formed by GlmU, a bi-functional enzyme. Inhibiting GlmU Uridyltransferase activity has been proven to be an effective anti-bacterial, but its similarity with human enzymes has been a deterrent to drug development. To develop Mtb selective hits, the Mtb GlmU substrate binding pocket was compared with structurally similar human enzymes to identify selectivity determining factors. Substrate binding pockets and conformational changes upon substrate binding were analyzed and MD simulations with substrates were performed to quantify crucial interactions to develop critical pharmacophore features. Thereafter, two strategies were applied to propose potent and selective bacterial GlmU Uridyltransferase domain inhibitors: (i) optimization of existing inhibitors, and (ii) identification by virtual screening. The binding modes of hits identified from virtual screening and ligand growing approaches were evaluated further for their ability to retain stable contacts within the pocket during 20 ns MD simulations. Hits that are predicted to be more potent than existing inhibitors and selective against human homologues could be of great interest for rejuvenating drug discovery efforts towards targeting the Mtb cell wall for antibacterial discovery.https://www.mdpi.com/1420-3049/27/9/2805MtbGlmUvirtual screeningmolecular dockingmolecular dynamics simulationsligand growing |
| spellingShingle | Manvi Singh Priya Kempanna Kavitha Bharatham Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches Molecules Mtb GlmU virtual screening molecular docking molecular dynamics simulations ligand growing |
| title | Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches |
| title_full | Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches |
| title_fullStr | Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches |
| title_full_unstemmed | Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches |
| title_short | Identification of Mtb GlmU Uridyltransferase Domain Inhibitors by Ligand-Based and Structure-Based Drug Design Approaches |
| title_sort | identification of mtb glmu uridyltransferase domain inhibitors by ligand based and structure based drug design approaches |
| topic | Mtb GlmU virtual screening molecular docking molecular dynamics simulations ligand growing |
| url | https://www.mdpi.com/1420-3049/27/9/2805 |
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