Interaction mechanism of Mycobacterium tuberculosis GroEL2 protein with macrophage Lectin-like, oxidized low-density lipoprotein receptor-1: An integrated computational and experimental study

Vinod, Vivek; Pushkaran, Anju Choorakottayil; Kumar, Anil; Mohan, C. Gopi; Biswas, Raja

doi:10.1016/j.bbagen.2020.129758

Cited by 7 publications

(4 citation statements)

References 45 publications

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“…Thus, identifying novel lead compounds against PD-L1 protein in blocking the PD-1/PD-L1 pathway is essential to combat this disease. The computational identification of lead compounds and sequence-structure-function relationship study was reported previously in several cases from our laboratory [41][42][43][44][45][46][47]. The present study involves the development of PD-L1 structure-based pharmacophore model, molecular docking-based VS and pharmacokinetics predictions for understanding the molecular mechanism of inhibition of the best VS leads for PD-L1 inhibition and its biological evaluation using different in vitro techniques.…”

Section: Resultsmentioning

confidence: 98%

Identification of a PD1/PD‐L1 inhibitor by structure‐based pharmacophore modelling, virtual screening, molecular docking and biological evaluation**

Pushkaran

Kumaran

et al. 2023

Molecular Informatics

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PD‐1/PD‐L1 is a critical druggable target for immunotherapy against sepsis. Chemoinformatics techniques involved the structure‐based 3D pharmacophore model development followed by virtual screening of small molecule databases to identify the small molecules against PD‐L1 pathway inhibition. Raltitrexed and Safinamide act as potent repurposed drugs, and three other Specs database compounds using in silico methods. These compounds were screened based on the pharmacophore fit score and binding affinity towards the active site of the PD‐L1 protein. In silico pharmacokinetic profiling of these screened compounds was done to test their biological activity. Next, experimental validation of the best four virtually screened hits was done in vitro for its hemocompatibility and cytotoxicity. Among these, Raltitrexed, Safinamide and Specs compound (AK‐968/40642641) effectively increased the proliferation of immune cells and IFN‐γ production. These compounds can act as potent PDL‐1 inhibitors for adjuvant therapy against sepsis.

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Section: Resultsmentioning

confidence: 98%

Identification of a PD1/PD‐L1 inhibitor by structure‐based pharmacophore modelling, virtual screening, molecular docking and biological evaluation**

Pushkaran

Kumaran

et al. 2023

Molecular Informatics

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“…As reported, LOX-1 serves as a scavenger receptor that mediates oxidized low‐density lipoprotein internalization through receptor-mediated endocytosis 24 . Besides, LOX-1 could act as a receptor that promotes the adhesion of Escherichia coli and Mycobacterium tuberculosis to macrophages and mediates the bacterial internalization 25 , 26 . Therefore, we speculated that LOX-1 might be an m 6 A-regulated target that modulated H. pylori attachment and invasion into gastric epithelial cells.…”

Section: Resultsmentioning

confidence: 99%

“…The subsequent studies showed that SRs not only could recognize damage-associated molecular patterns (DAMPs), like oxLDL, but could also bind to pathogen-associated molecular patterns (PAMPs), such as lipoteichoic acid (LTA) and lipopolysaccharide (LPS) of Gram-positive and Gram-negative bacteria, thus leading to the clearance of these pathogens through various mechanisms, like adhesion, endocytosis and phagocytosis 43 , 44 . In particular, surface-associated GroEL protein, a 60 kDa heat shock protein (HSP), was found to promote the adhesion of Escherichia coli and Mycobacterium tuberculosis to macrophages through binding with LOX-1 25 , 26 . In the present study, we further identified catalase as the H. pylori protein that binds to LOX-1 to initiate the invading process.…”

Section: Discussionmentioning

confidence: 99%

LOX-1 acts as an N6-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase

Zeng,

Xie,

Huang

et al. 2024

Nat Commun

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The role of N6-methyladenosine (m6A) modification of host mRNA during bacterial infection is unclear. Here, we show that Helicobacter pylori infection upregulates host m6A methylases and increases m6A levels in gastric epithelial cells. Reducing m6A methylase activity via hemizygotic deletion of methylase-encoding gene Mettl3 in mice, or via small interfering RNAs targeting m6A methylases, enhances H. pylori colonization. We identify LOX-1 mRNA as a key m6A-regulated target during H. pylori infection. m6A modification destabilizes LOX-1 mRNA and reduces LOX-1 protein levels. LOX-1 acts as a membrane receptor for H. pylori catalase and contributes to bacterial adhesion. Pharmacological inhibition of LOX-1, or genetic ablation of Lox-1, reduces H. pylori colonization. Moreover, deletion of the bacterial catalase gene decreases adhesion of H. pylori to human gastric sections. Our results indicate that m6A modification of host LOX-1 mRNA contributes to protection against H. pylori infection by downregulating LOX-1 and thus reducing H. pylori adhesion.

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“…Due to their size, the tubercle bacilli can reach the pulmonary alveoli, further becoming phagocytized by the alveolar macrophages (AM) [9,10]. The bacilli then multiply in the alveolar sacs.…”

Section: Introductionmentioning

confidence: 99%

Advanced drug delivery and therapeutic strategies for tuberculosis treatment

Nair,

Greeny,

Nandan

et al. 2023

J Nanobiotechnol

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Tuberculosis (TB) remains a significant global health challenge, necessitating innovative approaches for effective treatment. Conventional TB therapy encounters several limitations, including extended treatment duration, drug resistance, patient noncompliance, poor bioavailability, and suboptimal targeting. Advanced drug delivery strategies have emerged as a promising approach to address these challenges. They have the potential to enhance therapeutic outcomes and improve TB patient compliance by providing benefits such as multiple drug encapsulation, sustained release, targeted delivery, reduced dosing frequency, and minimal side effects. This review examines the current landscape of drug delivery strategies for effective TB management, specifically highlighting lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles, emulsion-based systems, carbon nanotubes, graphene, and hydrogels as promising approaches. Furthermore, emerging therapeutic strategies like targeted therapy, long-acting therapeutics, extrapulmonary therapy, phototherapy, and immunotherapy are emphasized. The review also discusses the future trajectory and challenges of developing drug delivery systems for TB. In conclusion, nanomedicine has made substantial progress in addressing the challenges posed by conventional TB drugs. Moreover, by harnessing the unique targeting abilities, extended duration of action, and specificity of advanced therapeutics, innovative solutions are offered that have the potential to revolutionize TB therapy, thereby enhancing treatment outcomes and patient compliance. Graphical Abstract

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Interaction mechanism of Mycobacterium tuberculosis GroEL2 protein with macrophage Lectin-like, oxidized low-density lipoprotein receptor-1: An integrated computational and experimental study

Cited by 7 publications

References 45 publications

Identification of a PD1/PD‐L1 inhibitor by structure‐based pharmacophore modelling, virtual screening, molecular docking and biological evaluation**

Identification of a PD1/PD‐L1 inhibitor by structure‐based pharmacophore modelling, virtual screening, molecular docking and biological evaluation**

LOX-1 acts as an N6-methyladenosine-regulated receptor for Helicobacter pylori by binding to the bacterial catalase

Advanced drug delivery and therapeutic strategies for tuberculosis treatment

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