Identification of novel efflux pump inhibitors for Neisseria gonorrhoeae via multiple ligand-based pharmacophores, e-pharmacophore, molecular docking, density functional theory, and molecular dynamics approaches

Jain, Neha; Sk, Md Fulbabu; Mishra, Amit; Kar, Parimal; Kumar, Amit

doi:10.1016/j.compbiolchem.2022.107682

Cited by 4 publications

(5 citation statements)

References 53 publications

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“…Chemical structures of selected EPIs inhibiting RND pumps in Gram-negative bacteria. Taken with permission from [83]: a [86], b [146], c [123], d [34,129], e [33], f [148], g [137], h [138], i [140], j [136], k [142], l [156], m [119], n [156], o [118], p [141], q [143], r [144], s [150], t [152], u [153], v [155], w [156], x [157]. Competitive inhibition [33] Pyranopyridine MBX3132 [131] HT within the RND transporter (T state) [34] >100 µg ml −1 [131] FQs, PIP 5ENO (MBX2319), 5ENP (MBX2931), 5ENQ (MBX3132), 5ENR (MBX3135) [34] Competitive inhibition [34] Pyridylpiperazine-based BDM88832 [148] Transmembrane domain of RND transporter (L state) [148] >500 µM >250 µM Pyridomycin 7OUK (BDM8885), 7OUL (BDM88832) [148] Allosteric inhibition [148] Antidepressant Amitriptyline [86] HT within the RND transporter (T state) [86] -CIP, NAL, norfloxacin [86] -Competitive inhibition/altered functional movements [86] Antipsychotic Chlorpromazine [86] HT within the RND transporter (T state)…”

Section: Mechanisms Of Inhibition Inhibition Of the Imp By Small Mole...mentioning

confidence: 99%

“…Subsequent docking calculations of typical AcrB substrates performed on the most stable AcrB-chlorpromazine and AcrB-amitriptyline complexes showed that these EPIs impede AcrB-mediated efflux by interfering with substrate binding. recent study on the RND pump MtrCDE of N. gonorrhoeae used a comprehensive pharmacophore-based approach, induced fit docking, MD simulations and MM-GBSA calculations to identify EPIs with improved pharmacology/safety profiles [146]. As a result of their investigation, five non-toxic bioactive chemicals (Fig.…”

Section: Mechanisms Of Inhibition Inhibition Of the Imp By Small Mole...mentioning

confidence: 99%

“…A recent study on the RND pump MtrCDE of N. gonorrhoeae used a comprehensive pharmacophore-based approach, induced fit docking, MD simulations and MM-GBSA calculations to identify EPIs with improved pharmacology/safety profiles [146]. As a result of their investigation, five non-toxic bioactive chemicals () extracted from the ZINC database [147] were identified as hits with binding affinity towards MtrD higher than that of the known inhibitors PAβN, D13-9001 and MBX2319.…”

Section: Mechanisms Of Inhibitionmentioning

confidence: 99%

Section: Mechanisms Of Inhibitionmentioning

confidence: 99%

Section: Mechanisms Of Inhibitionmentioning

confidence: 99%

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Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

et al. 2023

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Bacterial resistance to antibiotics has been long recognized as a priority to address for human health. Among all micro-organisms, the so-called multi-drug resistant (MDR) bacteria, which are resistant to most, if not all drugs in our current arsenal, are particularly worrisome. The World Health Organization has prioritized the ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa and Enterobacter species) pathogens, which include four Gram-negative bacterial species. In these bacteria, active extrusion of antimicrobial compounds out of the cell by means of ‘molecular guns’ known as efflux pumps is a main determinant of MDR phenotypes. The resistance-nodulation-cell division (RND) superfamily of efflux pumps connecting the inner and outer membrane in Gram-negative bacteria is crucial to the onset of MDR and virulence, as well as biofilm formation. Thus, understanding the molecular basis of the interaction of antibiotics and inhibitors with these pumps is key to the design of more effective therapeutics. With the aim to contribute to this challenge, and complement and inspire experimental research, in silico studies on RND efflux pumps have flourished in recent decades. Here, we review a selection of such investigations addressing the main determinants behind the polyspecificity of these pumps, the mechanisms of substrate recognition, transport and inhibition, as well as the relevance of their assembly for proper functioning, and the role of protein–lipid interactions. The journey will end with a perspective on the role of computer simulations in addressing the challenges posed by these beautifully complex machineries and in supporting the fight against the spread of MDR bacteria.

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Section: Mechanisms Of Inhibition Inhibition Of the Imp By Small Mole...mentioning

confidence: 99%

Section: Mechanisms Of Inhibition Inhibition Of the Imp By Small Mole...mentioning

confidence: 99%

Section: Mechanisms Of Inhibitionmentioning

confidence: 99%

Section: Mechanisms Of Inhibitionmentioning

confidence: 99%

Section: Mechanisms Of Inhibitionmentioning

confidence: 99%

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Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

et al. 2023

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Identification of DprE1 inhibitors for tuberculosis through integrated in-silico approaches

Dash,

Rathi,

Kumar

et al. 2024

Sci Rep

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Decaprenylphosphoryl-β-D-ribose-2′-epimerase (DprE1), a crucial enzyme in the process of arabinogalactan and lipoarabinomannan biosynthesis, has become the target of choice for anti-TB drug discovery in the recent past. The current study aims to find the potential DprE1 inhibitors through in-silico approaches. Here, we built the pharmacophore and 3D-QSAR model using the reported 40 azaindole derivatives of DprE1 inhibitors. The best pharmacophore hypothesis (ADRRR_1) was employed for the virtual screening of the chEMBL database. To identify prospective hits, molecules with good phase scores (> 2.000) were further evaluated by molecular docking studies for their ability to bind to the DprE1 enzyme (PDB: 4KW5). Based on their binding affinities (< − 9.0 kcal/mole), the best hits were subjected to the calculation of free-binding energies (Prime/MM-GBSA), pharmacokinetic, and druglikeness evaluations. The top 10 hits retrieved from these results were selected to predict their inhibitory activities via the developed 3D-QSAR model with a regression coefficient (R2) value of 0.9608 and predictive coefficient (Q2) value of 0.7313. The induced fit docking (IFD) studies and in-silico prediction of anti-TB sensitivity for these top 10 hits were also implemented. Molecular dynamics simulations (MDS) were performed for the top 5 hit molecules for 200 ns to check the stability of the hits with DprE1. Based on their conformational stability throughout the 200 ns simulation, hit 2 (chEMBL_SDF:357100) was identified as the best hit against DprE1 with an accepted safety profile. The MD results were also in accordance with the docking score, MM-GBSA value, and 3D-QSAR predicted activity. The hit 2 molecule, (N-(3-((2-(((1r,4r)-4-(dimethylamino)cyclohexyl)amino)-9-isopropyl-9H-purin-6-yl)amino)phenyl)acrylamide) could serve as a lead for the discovery of a novel DprE1 inhibiting anti-TB drug.

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Molecular docking, molecular dynamics simulation, and MM/PBSA analysis of ginger phytocompounds as a potential inhibitor of AcrB for treating multidrug-resistant Klebsiella pneumoniae infections

Sahoo,

Behera,

Gaur

et al. 2024

Journal of Biomolecular Structure and Dynamics

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Identification of novel efflux pump inhibitors for Neisseria gonorrhoeae via multiple ligand-based pharmacophores, e-pharmacophore, molecular docking, density functional theory, and molecular dynamics approaches

Cited by 4 publications

References 53 publications

Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

Tripartite efflux pumps of the RND superfamily: what did we learn from computational studies?

Identification of DprE1 inhibitors for tuberculosis through integrated in-silico approaches

Molecular docking, molecular dynamics simulation, and MM/PBSA analysis of ginger phytocompounds as a potential inhibitor of AcrB for treating multidrug-resistant Klebsiella pneumoniae infections

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