Combined MD/QTAIM techniques to evaluate ligand-receptor interactions. Scope and limitations

Rojas, Sebastián; Parravicini, Oscar; Vettorazzi, Marcela Cristina; Tosso, Rodrigo D.; Garro, Adriana; Gutiérrez, Lucas; Andújar, Sebastián Antonio; Enriz, Ricardo D.

doi:10.1016/j.ejmech.2020.112792

Cited by 25 publications

(45 citation statements)

References 59 publications

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“…Combined studies using molecular modeling techniques (docking calculations, MD simulation, and analysis per residue) were previously used by us in other biological systems. [70][71][72][73][74] CONFLICT OF INTERESTS…”

Section: Molecular Mechanics Generalized Born Surface Area (Mm-gbsa) Free-energy Decompositionmentioning

confidence: 96%

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Emam

Dahal

Singh

et al. 2021

Archiv der Pharmazie

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Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n).

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Section: Molecular Mechanics Generalized Born Surface Area (Mm-gbsa) Free-energy Decompositionmentioning

confidence: 96%

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Emam

Dahal

Singh

et al. 2021

Archiv der Pharmazie

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“…In order to evaluate in more details the molecular interactions of different molecular complexes, in the last stage of our study we carried out QTAIM calculations. This methodology was successfully applied in previous works [60][61][62][63][64][65]. Indeed, we have formerly reported and described the molecular interactions established in the active site of AChE and BChE when complexed with the well-known cholinesterase inhibitors RIV [66,67] and galantamine [68][69][70][71] and other ligands with great structural variability, including alkaloids [69,70], carbamates [67], 4-[(alkoxycarbonyl)amino]benzoates [66], and N-benzyl-2-phenylethanamine derivatives [72].…”

Section: Molecular Modeling Studiesmentioning

confidence: 99%

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

Magar

Parravicini

Štěpánková

et al. 2021

IJMS

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A series of 14 target benzyl [2-(arylsulfamoyl)-1-substituted-ethyl]carbamates was prepared by multi-step synthesis and characterized. All the final compounds were tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro, and the selectivity index (SI) was determined. Except for three compounds, all compounds showed strong preferential inhibition of BChE, and nine compounds were even more active than the clinically used rivastigmine. Benzyl {(2S)-1-[(2-methoxybenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5k), benzyl {(2S)-1-[(4-chlorobenzyl)sulfamoyl]-4-methylpentan-2-yl}carbamate (5j), and benzyl [(2S)-1-(benzylsulfamoyl)-4-methylpentan-2-yl]carbamate (5c) showed the highest BChE inhibition (IC50 = 4.33, 6.57, and 8.52 µM, respectively), indicating that derivatives 5c and 5j had approximately 5-fold higher inhibitory activity against BChE than rivastigmine, and 5k was even 9-fold more effective than rivastigmine. In addition, the selectivity index of 5c and 5j was approx. 10 and that of 5k was even 34. The process of carbamylation and reactivation of BChE was studied for the most active derivatives 5k, 5j. The detailed information about the mode of binding of these compounds to the active site of both BChE and AChE was obtained in a molecular modeling study. In this study, combined techniques (docking, molecular dynamic simulations, and QTAIM (quantum theory of atoms in molecules) calculations) were employed.

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“…QTAIM calculations are very useful tools for evaluating accurately and in detail the molecular interactions which stabilize ligand-receptor complexes 30 and can be used successfully in different biological systems [31][32][33][34][35] . In order to analyze the molecular interactions stabilizing the complexes of the target molecules and P-gp more quantitatively and with more detail, QM/MM calculations were performed, choosing the most representative complexes of the series.…”

Section: Charge Density Analysis Of Complexesmentioning

confidence: 99%

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

Laiolo¹,

Lanza²,

Parravicini³

et al. 2021

Preprint

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P-gp-associated multidrug resistance (MDR) is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone moiety favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

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Combined MD/QTAIM techniques to evaluate ligand-receptor interactions. Scope and limitations

Cited by 25 publications

References 59 publications

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Quinazoline‐tethered hydrazone: A versatile scaffold toward dual anti‐TB and EGFR inhibition activities in NSCLC

Novel Sulfonamide-Based Carbamates as Selective Inhibitors of BChE

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

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