Evidence map›Paper›PMID 38224406›Full record

ArticleJournal of molecular modeling2024

S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism.

Yutong Ge, Qing Luo, Ling Liu, Quanshan Shi, Zhigang Zhang, Xinru Yue, Lingkai Tang, Li Liang, Jianping Hu, Weiwei Ouyang

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Article in Journal of molecular modeling, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
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  3. The progress ofFrontiers in medicine · 2024
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4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Yutong Ge *Department of Thoracic Oncology, Affiliated Cancer Hospital, Guizhou Medical University, Guiyang, China.
Qing Luo *Faculty of Applied Sciences, Macao Polytechnic University, Macao, 999078, China.
Ling Liu *Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
Quanshan ShiKey Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
Zhigang ZhangDepartment of Thoracic Oncology, Affiliated Cancer Hospital, Guizhou Medical University, Guiyang, China.
Xinru YueKey Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
Lingkai TangKey Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
Li LiangKey Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
Jianping HuKey Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, School of Pharmacy, Chengdu University, Chengdu, 610106, China. hjpcdu@163.com.
Weiwei OuyangDepartment of Thoracic Oncology, Affiliated Cancer Hospital, Guizhou Medical University, Guiyang, China. ouyangww73@163.com.

Funding

Research and Development Plan in Key Areas of Guangdong Province 2022B1111050003
6 · The paper itself

Abstract

contextMycobacterial membrane proteins Large 3 (MmpL3) is responsible for the transport of mycobacterial acids out of cell membrane to form cell wall, which is essential for the survival of Mycobacterium tuberculosis (Mtb) and has become a potent anti-tuberculosis target. SQ109 is an ethambutol (EMB) analogue, as a novel anti-tuberculosis drug, can effectively inhibit MmpL3, and has completed phase 2b-3 clinical trials. Drug resistance has always been the bottleneck problem in clinical treatment of tuberculosis. The S288T mutant of MmpL3 shows significant resistance to the inhibitor SQ109, while the specific action mechanism remains unclear. The results show that MmpL3 S288T mutation causes local conformational change with little effect on the global structure. With MmpL3 bound by SQ109 inhibitor, the distance between D710 and R715 increases resulting in H-bond destruction, but their interactions and proton transfer function are still restored. In addition, the rotation of Y44 in the S288T mutant leads to an obvious bend in the periplasmic domain channel and an increased number of contact residues, reducing substrate transport efficiency. This work not only provides a possible dual drug resistance mechanism of MmpL3 S288T mutant but also aids the development of novel anti-tuberculosis inhibitors.

methodsIn this work, molecular dynamics (MD) and quantum mechanics (QM) simulations both were performed to compare inhibitor (i.e., SQ109) recognition, motion characteristics, and H-bond energy change of MmpL3 after S288T mutation. In addition, the WT_SQ109 complex structure was obtained by molecular docking program (Autodock 4.2); Molecular Mechanics/ Poisson Boltzmann Surface Area (MM-PBSA) and Solvated Interaction Energy (SIE) methods were used to calculate the binding free energies (∆G

Indexed as

EthylenediaminesMycobacterium tuberculosisProtonsAdamantaneCell MembraneIon ChannelsMolecular Docking SimulationAdamantaneEthylenediaminesIon ChannelsN-geranyl-N'-(2-adamantyl)ethane-1,2-diamineProtonsDrug resistanceH-bond networkMD simulationMmpL3Quantum mechanics

Identifiers

PMID38224406

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.