Pharmacophore-based screening and modification of amiloride analogs for targeting the NhaP-type cation-proton antiporter in <i>Vibrio cholerae</i>

Mourin, Muntahi; Bhattacharjee, Arittra; Wai, Alvan; Hausner, Georg; O'Neil, Joe D. J.; Dibrov, Pavel

doi:10.1139/cjm-2021-0074

Cited by 2 publications

(2 citation statements)

References 56 publications

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“…Specific modification in the side chain of amiloride analogs might make the compound a potential broad spectrum anti-microbial compound with safer ADMET properties and efficacy. Hence, further studies may contribute to the structural modification of these analogs devising a safer and more effective antiviral [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Microsecond molecular dynamics simulations revealed the inhibitory potency of amiloride analogs against SARS-CoV-2 E viroporin

et al. 2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes small envelope protein (E) that plays a major role in viral assembly, release, pathogenesis, and host inflammation. Previous studies demonstrated that pyrazine ring containing amiloride analogs inhibit this protein in different types of coronavirus including SARS-CoV-1 small envelope protein E (SARS-CoV-1 E). SARS-CoV-1 E has 93.42% sequence identity with SARS-CoV-2 E and shared a conserved domain NS3/small envelope protein (NS3_envE). Amiloride analog hexamethylene amiloride (HMA) can inhibit SARS-CoV-1 E. Therefore, we performed molecular docking and dynamics simulations to explore whether amiloride analogs are effective in inhibiting SARS-CoV-2 E. To do so, SARS-CoV-1 E and SARS-CoV-2 E proteins were taken as receptors while HMA and 3-amino-5-(azepan-1-yl)-N-(diaminomethylidene)-6-pyrimidin-5-ylpyrazine-2-carboxamide (3A5NP2C) were selected as ligands. Molecular docking simulation showed higher binding affinity scores of HMA and 3A5NP2C for SARS-CoV-2 E than SARS-CoV-1 E. Moreover, HMA and 3A5NP2C engaged more amino acids in SARS-CoV-2 E. Molecular dynamics (MD) simulation for 1 μs (1,000 ns) revealed that these ligands could alter the native structure of the proteins and their flexibility. Our study suggests that suitable amiloride analogs might yield a prospective drug against coronavirus disease 2019.

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Section: Discussionmentioning

confidence: 99%

Microsecond molecular dynamics simulations revealed the inhibitory potency of amiloride analogs against SARS-CoV-2 E viroporin

et al. 2021

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“…For molecular computer modeling, the Lvf•Hh structure was generated with Hyper-Chem 8.0.8 and docked to the crystallographic structure of DNA-Gyrase II (PBD: 6RKV) using the BIO-HPC Achilles Blind Docking Server online service [24]. The identified interactions between the low-molecular-weight ligand and the DNA-Gyrase II structure were visualized using PyMol and the Achilles Blind Docking Server [25].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

Exploring the Effects of Cramped-Impact-Type Mechanical Action on Active Pharmaceutical Ingredient (Levofloxacin)—Prospects for Pharmaceutical Applications

Uspenskaya,

Simutina,

Kuzmina

et al. 2023

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Mechanochemistry is one of the ten great discoveries of green chemistry methods for synthesizing new substances. A drug substance from the fluoroquinolone group was exposed to high-intensity mechanical impacts using a laboratory knife mill for 21 min and constantly monitored by analyzing samples extracted every 3 min with DLS, SLS, LALLS, 2D-LS, optical and digital microscopy, FTIR, and Spirotox methods. A dispersity phenomenon was detected in an area where catastrophic dislocations formed and multiplied via laser methods. The positive correlation between the temperature of deformation and stress was demonstrated, similar to a typical stress–strain curve of a Bochvar–Oding curve and Young’s modulus: the angular coefficient of the straight section to OX was tgα = 10 min−1. Z-Average, ζ-potential, and polydispersity index dependences were represented as discontinuous periodic oscillations analogous to the defect and impurity transitions near the dislocation core. Deformation r from the high-intensity mechanical impact resulted in covalent bonds showing hyper- and hypochromic effects under FTIR spectra, a bathochromic shift of the maximum, and an oscillation emission at 3240 cm−1. A 2D-LS fingerprint diagram obtained via the topological convolution of the light scattering matrix made it possible to distinguish the off-loading samples from the native substance. The investigation of the dissolution kinetics in water via laser diffraction led to conclusions about the limiting diffusion stage and the acceleration of the mechanoactivation of the solid body’s dissolution under both linear and plastic deformation. The acceleration of obsEa of the cell death process in the temperature range from 296 to 302 K indicated a significant (2.5-fold) decrease in the toxicity of the aqueous 9 mM (1:3) sample solution at 21 min compared to that of the native levofloxacin. Adherence to the mechanochemistry laws provides an opportunity for drug repositioning to change their brand status by identifying new physicochemical and biological properties.

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Pharmacophore-based screening and modification of amiloride analogs for targeting the NhaP-type cation-proton antiporter in Vibrio cholerae

Cited by 2 publications

References 56 publications

Microsecond molecular dynamics simulations revealed the inhibitory potency of amiloride analogs against SARS-CoV-2 E viroporin

Microsecond molecular dynamics simulations revealed the inhibitory potency of amiloride analogs against SARS-CoV-2 E viroporin

Exploring the Effects of Cramped-Impact-Type Mechanical Action on Active Pharmaceutical Ingredient (Levofloxacin)—Prospects for Pharmaceutical Applications

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