Drug target residence time: a misleading concept

Folmer, R.H.A.

doi:10.1016/j.drudis.2017.07.016

Cited by 52 publications

(60 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These observations (and numbers 4 and 5 in particular) are consistent with our claim that high dynamic occupancy under non-equilibrium conditions found in vivo depends first and foremost on fast k on , and further suggest that the rates of buildup of many of the targeted binding sites are ≥ 1×10 -5 s -1 (based on Table 1), assuming that k on was, in fact, wittingly or unwittingly optimized to k on_ss This contrasts with the claim of Dahl and Akrud [29] and Folmer [30] that the drugs were optimized on the basis of K d (noting that Folmer acknowledges the greater contribution of fast k on over slow k off to drug success [30]).…”

Section: Resultssupporting

confidence: 89%

Biodynamics: A novel quasi-first principles theory on the fundamental mechanisms of cellular function/dysfunction and the pharmacological modulation thereof

Selvaggio

Pearlstein

2018

Preprint

View full text Add to dashboard Cite

15Cellular function depends on heterogeneous dynamic intra-, inter-, and supramolecular structure-16 function relationships. However, the specific mechanisms by which cellular function is 17 transduced from molecular systems, and by which cellular dysfunction arises from molecular 18 dysfunction are poorly understood. We proposed previously that cellular function manifests as a 19 molecular form of analog computing, in which specific time-dependent state transition fluxes 20 within sets of molecular species ("molecular differential equations" (MDEs)) are sped and 21 slowed in response to specific perturbations (inputs). In this work, we offer a theoretical 22 treatment of the molecular mechanisms underlying cellular analog computing (which we refer to 23 as "biodynamics"), focusing primarily on non-equilibrium (dynamic) intermolecular state 24 transitions that serve as the principal means by which MDE systems are solved (the molecular 25 equivalent of mathematical "integration"). Under these conditions, bound state occupancy is 26 governed by and , together with the rates of binding partner buildup and decay. 27Achieving constant fractional occupancy over time depends on: 1) equivalence between k on and 28 the rate of binding site buildup); 2) equivalence between and the rate of binding site decay; 29 and 3) free ligand concentration relative to / (n  K d , where n is the fold increase in 30 binding partner concentration needed to achieve a given fractional occupancy). Failure to satisfy 31 these conditions results in fractional occupancy well below that corresponding to n  K d . The 32implications of biodynamics for cellular function/dysfunction and drug discovery are discussed. 33 34 35 45 46 Enzyme-substrate: -( ) 47 48 where represents the rates of non-equilibrium occupancy buildup and decay of state k ( )/ 49 from one or more predecessor to one or more successor states. State transition rates are governed 50 by adjustable barriers originating from intra-or intermolecular interactions (which we referred to 51 as "intrinsic rates") and time-dependent changes in the concentrations or number densities of the 52 participating species (which we referred to as "extrinsic rates") [1]. Molecular populations "flow" 53 over time in a transient (Markovian) fashion from one specific structural state to another (Fig 1) 54 in response to production/degradation or translocation-driven changes in the levels of the 55 participating species. 56 Fig 1. (A) Markovian state transition behavior exemplified for the human cardiac ether-a-57 go-go related gene (hERG) potassium channel between closed (C1, C2, and C3), open (O) 58 and inactivated states (I) underlying the state probability curves in (B) [4]. The rate 59 constants are labeled with Greek letters. (B) Molecular populations of hERG "flow" from 60 one specific state to another based on intrinsic voltage-dependent rates of entry and exit. 61 Multiple fluxes occur in parallel between specific states, speeding and slowing in response 62 to dynamic perturbations. For ex...

show abstract

Section: Resultssupporting

confidence: 89%

Biodynamics: A novel quasi-first principles theory on the fundamental mechanisms of cellular function/dysfunction and the pharmacological modulation thereof

Selvaggio

Pearlstein

2018

Preprint

View full text Add to dashboard Cite

show abstract

“…By proving that the SirReal core, which is sufficient to induce the structural rearrangement of Sirt2'sa ctive site, [24a] is the main driver of the slow off rate for this class of inhibitors, we have been able to add af urtheri mportant piece of evidence that conformational adaption upon ligand binding greatly increasest he residence time of the bound ligand,c ulminating in highly selective and high-affinity drug-targeti nteractions. There is an emerging debate whether long residence time (k off ) is really ab etter predictor of success in drug development than mere potency or affinity (IC 50 or K d ); [33] our study suggests that al ongr esidence time as ac onsequence of an induced-fit mechanism can be an importantd river of target selectivity, which is one of the most crucial parameters in modernd rug discovery.…”

Section: Resultsmentioning

confidence: 79%

Validation of Slow Off-Kinetics of Sirtuin Rearranging Ligands (SirReals) by Means of the Label-Free Electrically Switchable Nanolever Technology

Schiedel¹,

Daub²,

Itzen³

et al. 2019

Preprint

View full text Add to dashboard Cite

Recently, we have discovered the sirtuin rearranging ligands (SirReals) as a novel class of highly potent and selective inhibitors of the NAD+-dependent lysine deacetylase Sirt2. In previous studies, using a biotinylated SirReal analogue in combination with biolayer interferometry, we observed a slow dissociation rate of the inhibitor-enzyme complex, which had been postulated to be the key to the high affinity and selectivity of SirReals. However, for the attachment of biotin to the SirReal core, we introduced a triazole as a linking moiety, which was shown by X-ray co-crystallography to interact with Arg97 of the cofactor binding loop. This study now is directed to answer the question, whether the observed long residence time of the SirReals is induced mainly by triazole incorporation or is an inherent characteristic of the SirReal inhibitor core. Therefore, we used the novel label-free switchSENSE® technology, based on electrically switchable DNA nanolevers, to validate that the long residence time of the SirReals is caused by the core scaffold.<br>

show abstract

“…By proving that the SirReal core, which is sufficient to induce the structural rearrangement of Sirt2′s active site, is the main driver of the slow off rate for this class of inhibitors, we have been able to add a further important piece of evidence that conformational adaption upon ligand binding greatly increases the residence time of the bound ligand, culminating in highly selective and high‐affinity drug–target interactions. There is an emerging debate whether long residence time ( k off ) is really a better predictor of success in drug development than mere potency or affinity (IC 50 or K d ); our study suggests that a long residence time as a consequence of an induced‐fit mechanism can be an important driver of target selectivity, which is one of the most crucial parameters in modern drug discovery.…”

Section: Resultsmentioning

confidence: 86%

Validation of the Slow Off‐Kinetics of Sirtuin‐Rearranging Ligands (SirReals) by Means of Label‐Free Electrically Switchable Nanolever Technology

et al. 2020

View full text Add to dashboard Cite

We have discovered the sirtuin‐rearranging ligands (SirReals) to be highly potent and selective inhibitors of the NAD+‐dependent lysine deacetylase Sirt2. Using a biotinylated SirReal in combination with biolayer interferometry, we previously observed a slow dissociation rate of the inhibitor–enzyme complex; this had been postulated to be the key to the high affinity and selectivity of SirReals. However, to attach biotin to the SirReal core, we introduced a triazole as a linking moiety; this was shown by X‐ray co‐crystallography to interact with Arg97 of the cofactor binding loop. Herein, we aim to elucidate whether the observed long residence time of the SirReals is induced mainly by triazole incorporation or is an inherent characteristic of the SirReal inhibitor core. We used the novel label‐free switchSENSE® technology, which is based on electrically switchable DNA nanolevers, to prove that the long residence time of the SirReals is indeed caused by the core scaffold.

show abstract

Drug target residence time: a misleading concept

Cited by 52 publications

References 18 publications

Biodynamics: A novel quasi-first principles theory on the fundamental mechanisms of cellular function/dysfunction and the pharmacological modulation thereof

Biodynamics: A novel quasi-first principles theory on the fundamental mechanisms of cellular function/dysfunction and the pharmacological modulation thereof

Validation of Slow Off-Kinetics of Sirtuin Rearranging Ligands (SirReals) by Means of the Label-Free Electrically Switchable Nanolever Technology

Validation of the Slow Off‐Kinetics of Sirtuin‐Rearranging Ligands (SirReals) by Means of Label‐Free Electrically Switchable Nanolever Technology

Contact Info

Product

Resources

About