Target–drug interactions: first principles and their application to drug discovery

Núñez, Sara; Venhorst, Jennifer; Kruse, Chris G.

doi:10.1016/j.drudis.2011.06.013

Cited by 151 publications

(89 citation statements)

References 72 publications

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“…However, it is by now well-recognized that one of the most pertinent factors for sustained drug efficacy and safety is not just its affinity, but possibly even more so, the mean lifetime of the protein-ligand complex (1)(2)(3). The latter property is strictly related to the time during which the ligand remains in the binding site (1,2), and is typically expressed by its inverse, the dissociation rate k off (2). In principle k off should be amenable to calculations through all-atom molecular dynamics (MD) simulations.…”

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confidence: 99%

“…Even with the most modern purpose-built supercomputers or massive distributed computing, one can barely reach the timescale of milliseconds (3). Unfortunately most of the reported ligand-protein dissociation times far exceed this timescale (2). These timescales can be reached either by transition path sampling methods (8,9), quasiclassical approximations (10), by the construction of Markov state models (11,12), or through carefully designed enhanced sampling methods (8,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) that make accessible the timescale of seconds and beyond in a controlled and accurate way.…”

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confidence: 99%

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Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps

Tiwary

Limongelli

Salvalaglio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

345

428

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The ability to predict the mechanisms and the associated rate constants of protein-ligand unbinding is of great practical importance in drug design. In this work we demonstrate how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin-benzamidine system. Protein, ligand, and solvent are described with full atomic resolution. Using metadynamics, multiple unbinding trajectories that start with the ligand in the crystallographic binding pose and end with the ligand in the fully solvated state are generated. The unbinding rate k off is computed from the mean residence time of the ligand. Using our previously computed binding affinity we also obtain the binding rate k on . Both rates are in agreement with reported experimental values. We uncover the complex pathways of unbinding trajectories and describe the critical ratelimiting steps with unprecedented detail. Our findings illuminate the role played by the coupling between subtle protein backbone fluctuations and the solvation by water molecules that enter the binding pocket and assist in the breaking of the shielded hydrogen bonds. We expect our approach to be useful in calculating rates for general protein-ligand systems and a valid support for drug design.protein-ligand unbinding | kinetics | enhanced sampling | drug design U nderstanding the thermodynamics and kinetics of proteinligand interactions is of paramount relevance in the early stages of drug discovery (1-3). So far the major emphasis has been placed on predicting the most likely binding pose as determined by the highest binding affinity (4, 5). In contrast, it has not been possible to predict the pathways for unbinding and the associated rates. However, it is by now well-recognized that one of the most pertinent factors for sustained drug efficacy and safety is not just its affinity, but possibly even more so, the mean lifetime of the protein-ligand complex (1-3). The latter property is strictly related to the time during which the ligand remains in the binding site (1, 2), and is typically expressed by its inverse, the dissociation rate k off (2). In principle k off should be amenable to calculations through all-atom molecular dynamics (MD) simulations. These simulations could give detailed and useful insights into the atomic interactions at work during unbinding, especially in the ephemeral but kinetically most relevant transition state ensemble (TSE) (6, 7). Such information is of great value in designing modifications of the ligand that might improve its pharmaceutical properties.However, despite the potential of MD simulations no such calculation has yet been reported. This is a consequence of the limited timescales of MD simulations. Even with the most modern purpose-built supercomputers or massive distributed computing, one can barely reach the timescale of milliseconds (3). Unfortunately most of the reported ligand-protein dissociation times fa...

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confidence: 99%

mentioning

confidence: 99%

Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps

Tiwary

Limongelli

Salvalaglio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

345

428

View full text Add to dashboard Cite

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“…Thus, replacement of the octanol component by artificial phospholipid bilayer systems or even by biological membranes is justified. Recently, K p values obtained in this manner were used as a 'correction factor' to understand better the potential contribution of the membrane to the binding of bronchodilators and of other β 2 -adrenoreceptor ligands to this receptor [21].Participation of the membrane in the binding process A popular strategy in medicinal chemistry is to add hydrophobic functional groups to the skeleton of a lead compound [39], largely because drug molecules in solution are enclosed by an organized network of water molecules. When a drug is hydrophobic, removal of those water molecules (which is also denoted as 'desolvation') during the binding process provides a substantial contribution to the affinity of the drug [40,41].…”

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confidence: 99%

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Vauquelin

2016

Brit J Clinical Pharma

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The time course of the beneficial pharmacological effect of a drug has long been considered to depend merely on the temporal fluctuation of its free concentration. Only in the last decade has it become widely accepted that target-binding kinetics can also affect in vivo pharmacological activity. Although current reviews still essentially focus on genuine dissociation rates, evidence is accumulating that additional micro-pharmacokinetic (PK) and -pharmacodynamic (PD) mechanisms, in which the cell membrane plays a central role, may also increase the residence time of a drug on its target. The present review provides a compilation of otherwise widely dispersed information on this topic. The cell membrane can intervene in drug binding via the following three major mechanisms: (i) by acting as a sink/repository for the drug; (ii) by modulating the conformation of the drug and even by participating in the binding process; and (iii) by facilitating the approach (and rebinding) of the drug to the target. To highlight these mechanisms, we focus on drugs that are currently used in clinical therapy, such as the antihypertensive angiotensin II type 1 receptor antagonist candesartan, the atypical antipsychotic agent clozapine and the bronchodilator salmeterol. Although the role of cell membranes in PK-PD modelling is gaining increasing interest, many issues remain unresolved. It is likely that novel biophysical and computational approaches will provide improved insights in the near future. IntroductionThe pharmacokinetic (PK) and pharmacodynamic (PD) properties of a drug are determinants of its efficacy and the duration of its clinical action [1]. PK and PD have long been considered to be separate disciplines, and the time course of the pharmacological effect of a drug has essentially been considered in terms of the temporal fluctuation of its free concentration [2]. In accordance with this principle, the frequently observed time lag between the concentration of a drug in the systemic circulation and its effect was initially attributed to slow equilibration between the plasma and a hypothetical target-surrounding 'effect compartment' [3]. By contrast, preclinical screening studies traditionally aim to optimize drug candidates in terms of only their efficacy and potency (i.e. PD properties). Inherent to this practice is the proposal that drug-target interactions are adequately described by equilibrium equations and, hence, that association and dissociation rates play only subordinate roles. In addition to a few noteworthy exceptions [4,5], it is only in the last decade that it has become fashionable to include binding kinetics as an additional criterion for clinical efficacy. This insight was largely sparked by the seminal articles by Swinney [6] and Copeland et al. [7]. The numerous review articles that have been published subsequently have focused mainly on long residence times. This property is now recognized to play a key role with respect to the clinical British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016...

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“…Slowly dissociating antagonist compounds give a higher receptor occupancy due to their increased residence time, so the wash step which effectively removes any unbound ligand will favour slowly dissociating compounds. [24][25][26] Despite the higher potency of the quinoline 27, the lower calculated logP of the 3-pyridyl derivative 35 yielded a compound with a higher LiPE value than the quinoline, suggesting that it was likely to be a better 'drug-like' candidate based on its calculated physicochemical properties. Furthermore, the calculated pharmacokinetic properties of 35 were predominantly within the recommended values as suggested by Schrödinger, and with similar values to 95% of known drugs ( Table 4).…”

Section: Resultsmentioning

confidence: 99%

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists

O'Brien-Brown

Jackson

Reekie

et al. 2017

European Journal of Medicinal Chemistry

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ABSTRACT:Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 3 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X 7 R antagonists.

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Target–drug interactions: first principles and their application to drug discovery

Cited by 151 publications

References 72 publications

Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps

Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps

Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists

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