Medicinal chemistry: an effect of a desolvation penalty of an amide group in the development of kinase inhibitors

Dobiáš, Juraj; Ondruš, Marek; Hlaváč, Matúš; Murár, Miroslav; Kóňa, Juraj; Addová, Gabriela; Boháč, Andrej

doi:10.1007/s11696-018-0576-6

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…The additional reason for the lower activity of compound 8d could be the desolvation and the rotation penalty caused by a –CH 2 OH group. Desolvation penalty effect is a subject of recent publication [ 81 ].…”

Section: Studies At the Level Of Isolated Enzymes And Free Radical Models In Vitro And In Silico: Sarmentioning

confidence: 99%

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

et al. 2021

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Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.

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Section: Studies At the Level Of Isolated Enzymes And Free Radical Models In Vitro And In Silico: Sarmentioning

confidence: 99%

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

et al. 2021

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“…Desolvation penalty effect has been a subject of our recent publication. 14 Derivatives OTI-(8,9) (-CONH2, -COOH, resp.) revealed 2 to 3-fold lower inhibitory activity in comparison to OTI-7 (-CN).…”

Section: Determination Of Enzyme Inhibitory Activitiesmentioning

confidence: 99%

Novel substituted N-benzyl(oxotriazinoindole) inhibitors of aldose reductase exploiting ALR2 unoccupied interactive pocket

Hlaváč

Kovacikova

Prnová

et al. 2021

Bioorganic & Medicinal Chemistry

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Recently we have developed novel oxotriazinoindole inhibitors (OTIs) of aldose reductase (ALR2), characterized by high efficacy and selectivity. Herein we describe novel OTI derivatives design of which is based on implementation of additional intermolecular interactions within an unoccupied pocket of the ALR2 enzyme. Four novel derivatives, OTI-(7-10), of the previously developed N-benzyl(oxotriazinoindole) inhibitor OTI-6 were synthetized and screened. All of them revealed 2 to 6 times higher ALR2 inhibitory efficacy when compared to their non-substituted lead compound OTI-6. Moreover, the most efficient ALR2 inhibitor OTI-7 (IC50 = 76 nM) possesses remarkably high inhibition selectivity (SF ≥ 1300) in relation to structurally related aldehyde reductase (ALR1). Derivatives OTI-(8-10) bearing the substituents -CONH2, -COOH and -CH2OH, possess 2-3 times lower inhibitory efficacy compared to OTI-7, but better than the reference inhibitor OTI-6. Desolvation penalty is suggested as a possible factor responsible for the drop in ALR2 inhibitory efficacy observed for derivatives OTI-(8-10) in comparison to OTI-7.

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“…Nevertheless, several studies have investigated the effect of solvation on stacking interactions and the resulting implications on thermodynamic properties (Kolár et al, 2011 ; Lee et al, 2019 ; Loeffler et al, 2020 ). In general, assessment of the desolvation penalty is crucial in drug design as it can reveal why certain molecules do not reflect the expected gain in binding affinity (Biela et al, 2012 ; Dobiaš et al, 2019 ; Loeffler et al, 2020 ). Therefore, a combination of approaches is inevitable to understand the energetics of molecules and to interpret and optimize SAR studies (Loeffler et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Conformational Shifts of Stacked Heteroaromatics: Vacuum vs. Water Studied by Machine Learning

et al. 2021

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Stacking interactions play a crucial role in drug design, as we can find aromatic cores or scaffolds in almost any available small molecule drug. To predict optimal binding geometries and enhance stacking interactions, usually high-level quantum mechanical calculations are performed. These calculations have two major drawbacks: they are very time consuming, and solvation can only be considered using implicit solvation. Therefore, most calculations are performed in vacuum. However, recent studies have revealed a direct correlation between the desolvation penalty, vacuum stacking interactions and binding affinity, making predictions even more difficult. To overcome the drawbacks of quantum mechanical calculations, in this study we use neural networks to perform fast geometry optimizations and molecular dynamics simulations of heteroaromatics stacked with toluene in vacuum and in explicit solvation. We show that the resulting energies in vacuum are in good agreement with high-level quantum mechanical calculations. Furthermore, we show that using explicit solvation substantially influences the favored orientations of heteroaromatic rings thereby emphasizing the necessity to include solvation properties starting from the earliest phases of drug design.

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Medicinal chemistry: an effect of a desolvation penalty of an amide group in the development of kinase inhibitors

Cited by 3 publications

References 20 publications

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Novel substituted N-benzyl(oxotriazinoindole) inhibitors of aldose reductase exploiting ALR2 unoccupied interactive pocket

Conformational Shifts of Stacked Heteroaromatics: Vacuum vs. Water Studied by Machine Learning

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