Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

Shahraki, Omolbanin; Edraki, Najmeh; Khoshneviszadeh, Mehdi; Zargari, Farshid; Ranjbar, Sara; Saso, Luciano; Firuzi, Omidreza; Miri, Ramin

doi:10.2147/dddt.s119995

Cited by 22 publications

(5 citation statements)

References 45 publications

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“…The technical possibilities of molecular dynamics simulations mean that MD simulations of P-gp have been conducted with a variety of simulation conditions. To date, independent simulation studies of P-gp structures have used a range of different force fields, including several from the AMBER, ,,− CHARMM, ,− GROMOS, ,,,,,− OPLS, , and MARTINI , families of force fields. In many cases, the choice of force field is governed by the familiarity of the researcher with the particular force field or its associated MD package.…”

Section: Introductionmentioning

confidence: 99%

Effect of the Force Field on Molecular Dynamics Simulations of the Multidrug Efflux Protein P-Glycoprotein

Wang

O’Mara

2021

J. Chem. Theory Comput.

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Molecular dynamics (MD) simulations have been used extensively to study P-glycoprotein (P-gp), a flexible multidrug transporter that is a key player in the development of multidrug resistance to chemotherapeutics. A substantial body of literature has grown from simulation studies that have employed various simulation conditions and parameters, including AMBER, CHARMM, OPLS, GROMOS, and coarsegrained force fields, drawing conclusions from simulations spanning hundreds of nanoseconds. Each force field is typically parametrized and validated on different data and observables, usually of small molecules and peptides; there have been few comparisons of force field performance on large protein− membrane systems. Here we compare the conformational ensembles of P-gp embedded in a POPC/cholesterol bilayer generated over 500 ns of replicate simulation with five force fields from popular biomolecular families: AMBER 99SB-ILDN, CHARMM 36, OPLS-AA/L, GROMOS 54A7, and MARTINI. We find considerable differences among the ensembles with little conformational overlap, although they correspond to similar extents to structural data obtained from electron paramagnetic resonance and crosslinking studies. Moreover, each trajectory was still sampling new conformations at a high rate after 500 ns of simulation, suggesting the need for more sampling. This work highlights the need to consider known limitations of the force field used (e.g., biases toward certain secondary structures) and the simulation itself (e.g., whether sufficient sampling has been achieved) when interpreting accumulated results of simulation studies of P-gp and other transport proteins.

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Section: Introductionmentioning

confidence: 99%

Effect of the Force Field on Molecular Dynamics Simulations of the Multidrug Efflux Protein P-Glycoprotein

Wang

O’Mara

2021

J. Chem. Theory Comput.

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“…The work of Shahraki et al [ 52 ] is a good example of what has just been said, as the authors used MD simulations to further investigate the possible binding sites of the most active 5-oxo-hexahydroquinoline derivatives according to the in vitro P-gp-mediated multidrug resistance reversal assay. The results from MD show that the active compound could be stabilized by the formation of H-bonds with some protein residues and by hydrophobic and arene-π interactions.…”

Section: Structure-based Approachesmentioning

confidence: 99%

Recent Advances on P-Glycoprotein (ABCB1) Transporter Modelling with In Silico Methods

Lagares

Novič

2022

IJMS

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ABC transporters play a critical role in both drug bioavailability and toxicity, and with the discovery of the P-glycoprotein (P-gp), this became even more evident, as it plays an important role in preventing intracellular accumulation of toxic compounds. Over the past 30 years, intensive studies have been conducted to find new therapeutic molecules to reverse the phenomenon of multidrug resistance (MDR) ), that research has found is often associated with overexpression of P-gp, the most extensively studied drug efflux transporter; in MDR, therapeutic drugs are prevented from reaching their targets due to active efflux from the cell. The development of P-gp inhibitors is recognized as a good way to reverse this type of MDR, which has been the subject of extensive studies over the past few decades. Despite the progress made, no effective P-gp inhibitors to reverse multidrug resistance are yet on the market, mainly because of their toxic effects. Computational studies can accelerate this process, and in silico models such as QSAR models that predict the activity of compounds associated with P-gp (or analogous transporters) are of great value in the early stages of drug development, along with molecular modelling methods, which provide a way to explain how these molecules interact with the ABC transporter. This review highlights recent advances in computational P-gp research, spanning the last five years to 2022. Particular attention is given to the use of machine-learning approaches, drug–transporter interactions, and recent discoveries of potential P-gp inhibitors that could act as modulators of multidrug resistance.

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“…One such modification is fusing a cyclohexanone ring to form hexahydroquinoline (HHQ), in which the orientation of the carbonyl group of the ester substituent at the 5-position in the 1,4-DHP ring has been fixed. This class of compounds has been shown to have calcium-channel antagonistic activity (Aygu ¨n Cevher et al, 2019), inhibit the multidrug-resistance transporter (MDR) (Shahraki et al, 2017(Shahraki et al, , 2020, as well as possessing antiinflammatory and stem-cell differentiation properties, and have been implicated in slowing neurodegenerative disorders (Trippier et al, 2013). Recently, specific substitutions of the cyclohexenone ring were found to have distinct selectivity profiles to different calcium channel subtypes (Schaller et al, 2018).…”

Section: Chemical Contextmentioning

confidence: 99%

Synthesis, crystal structures, and Hirshfeld analysis of three hexahydroquinoline derivatives

Steiger

Oliver

et al. 2022

Acta Cryst E

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Three hexahydroquinoline derivatives were synthesized and crystallized in an effort to study the structure–activity relationships of these calcium-channel antagonists. The derivatives are ethyl 4-(2-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C22H27NO4, (I), ethyl 4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C22H27NO4, (II), and ethyl 4-(3,4-dihydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, C21H24NO5, (III). In these hexahydroquinoline derivatives, common structural features such as a flat-boat conformation of the 1,4-dihydropyridine (1,4-DHP) ring, an envelope conformation of the fused cyclohexanone ring, and a substituted phenyl group at the pseudo-axial position are retained. Hydrogen bonds are the main contributors to the packing of the molecules in these crystals.

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Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

Cited by 22 publications

References 45 publications

Effect of the Force Field on Molecular Dynamics Simulations of the Multidrug Efflux Protein P-Glycoprotein

Effect of the Force Field on Molecular Dynamics Simulations of the Multidrug Efflux Protein P-Glycoprotein

Recent Advances on P-Glycoprotein (ABCB1) Transporter Modelling with In Silico Methods

Synthesis, crystal structures, and Hirshfeld analysis of three hexahydroquinoline derivatives

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