Unbinding Kinetics of a p38 MAP Kinase Type II Inhibitor from Metadynamics Simulations

Casasnovas, Rodrigo; Limongelli, Vittorio; Tiwary, Pratyush; Carloni, Paolo; Parrinello, Michele

doi:10.1021/jacs.6b12950

Cited by 204 publications

(240 citation statements)

References 70 publications

(173 reference statements)

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“…Our study suggests that using only the distance between the ligand and the binding cavity on p38α fails to describe the unbinding process properly, which has also been reported by others recently. 33 Remarkably, for well-converged metadynamics FE simulations ( Figure S1), the choice of two different sets of CVs lead to similar results in terms of thermodynamics and kinetics, which could be considered as a validation of our approach.…”

Section: Selections Of Simulation Models and Slow Motionsmentioning

confidence: 66%

“…applied metadynamics and Markov state model to compute the kinetic rates of one inhibitor unbinding from p38α with residence time of a few seconds. 33 A systematic study of a series of inhibitors spanning a wide range of unbinding kinetics and exhibiting diverse structural features could provide further guidance to therapeutic design. However, it is quite challenging and even prohibited to compute the kinetic rates accurately for complex systems and slower unbinding processes with currently available methodologies and compute resources.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Unbinding Kinetics Relationship of p38α MAPK Inhibitors

Tan²,

Xie

2019

Preprint

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Rational Drug Design still faces a major hurdle for the prediction of drug efficacy in vivo solely based on its binding affinity for the target in vitro. The traditional perspective has proven to be inadequate as it lacks the consideration of essential aspects such as pharmacokinetics and binding kinetics in determining drug efficacy and toxicity. Residence time, the average lifetime of drug-target complex, has gained broader recognition as a better predictor for lead optimization.Long residence time could contribute to sustained pharmacological effect and may mitigate offtarget toxicity as well. To unravel the underlining mechanism for variation of residence time and determine the ligand features governing the unbinding kinetics, unbinding kinetics of two distinct type II inhibitors of p38α MAP kinase were investigated and compared by molecular dynamics and metadynamics simulation approaches. Free energy landscape of key motions associated with unbinding was constructed for both inhibitors. Multiple unbinding pathways and rebinding were revealed during the drug-target dissociation process of faster unbinder Lig3 and slower unbinder Lig8 respectively, suggesting a novel mechanism of unbinding kinetics. This comparative study implies that hydrophobic and hydrogen-bonding interactions in the R1 group of ligands are crucial for slow unbinding. Such kind of structure-kinetics relationship approaches could also be applied to predict unbinding pathways and kinetics of many other small molecules, and facilitate the design of efficient kinase inhibitors.

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Section: Selections Of Simulation Models and Slow Motionsmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Structure-Unbinding Kinetics Relationship of p38α MAPK Inhibitors

Tan²,

Xie

2019

Preprint

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“…Metadynamics-based protocol was developed to investigate the unbinding mechanism of an inhibitor of the pharmacologically relevant target p38 MAP kinase. The result of calculations showed that the salvation of the ligand and of the active site played crucial roles in the unbinding process and demonstrating that metadynamics could be a powerful tool in designing new drugs with engineered binding/unbinding kinetics [25].…”

Section: Introductionmentioning

confidence: 99%

3D Pharmacophore-based Virtual Screening, Docking Approaches toward the Discovery of Novel HPPD Inhibitors

Fu¹,

Sun²,

Yi³

et al. 2017

Preprint

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p-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only the useful molecular target in treating life-threatening tyrosinemia type I, but also an important target for chemical herbicides. A combined in silico structure-based pharmacophore and molecular docking based virtual screening were performed to identify novel potential HPPD inhibitors. The complex based pharmacophore model (CBP) with 0.721 of ROC used for screening compound showed remarkable ability to retrieve known active ligands from decoy molecule. The ChemDiv database was screened using CBP-Hypo2 as a 3D query, and the best-fit hits subjected to molecular docking with two methods of LibDock and CDOCKER in Accelrys Discovery Studio 2.5(DS 2.5) to discern interactions with key residues at the active site of HPPD. 4 Compounds with top rank in HipHop model and well-known binding model were finally chosen as identification of lead compounds with potentially inhibitory effects on active site of target. The results provided powerful insight to the development of novel HPPD inhibitors herbicides using computational techniques.

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“…11-13 These give direct observations of kinetic information [14][15][16][17][18][19][20] -not just the unbinding rate constant, which experiments can measure reliably, but also other entities which are very hard to obtain from experiments, such as unbinding pathways, intermediate states, their residence times, and the ratedetermining steps.…”

mentioning

confidence: 99%

“…22 We expect and find that considering the dimer instead of tetramer brings down the residence time from more than a day to around a second, which is a timescale regime where the enhanced sampling methods of this work have been shown to be reliable. [14][15][16] Note that there is no fundamental reason why these methods should not work for much longer timescales, and this will be the subject of future investigations. For the tetrameric biotin-streptavidin system the WT and N23A have been reported to have k of f of 4.4 ± 0.3 × 10…”

mentioning

confidence: 99%

Molecular determinants and bottlenecks in the unbinding dynamics of biotin-streptavidin

Tiwary

2017

Preprint

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Biotin-streptavidin is a very popular system used to gain insight into protein-ligand interactions. In its tetrameric form, it is well-known for its extremely long residence times, being one of the strongest known non-covalent interactions in nature, and is heavily used across the biotechnological industry. In this work we gain understanding into the molecular determinants and bottlenecks in the unbinding of the dimeric biotinstreptavidin system in its wild type and with N23A mutation. Using new enhanced sampling methods with full atomistic resolution, we reproduce the variation caused by N23A mutation in experimentally reported residence time. We also answer a longstanding question regarding cause/effect in the coupled events of bond stretching and bond hydration during unbinding and establish that in this system, it is the bond stretching and not hydration which forms the bottleneck in the early parts of the unbinding. We believe these calculations represent a step forward in the use of atomistic simulations to study pharmacodynamics. An improved understanding of biotin-streptavidin unbinding dynamics should also have direct benefits in biotechnological and nanobiotechnological applications.The interaction of streptavidin with biotin in the homotetramer form is one of the strongest known noncovalent interactions in nature. 1-4 This system forms a central component of countless biological, biotechnological and nano-biotechnological applications, and has long been used as a model system to understand the molecular basis of high affinity binding. 5,6 Designing specific mutations in streptavidin allows tailoring a wide range of affinities and rate constants 7 as needed for diverse practical applications. Further, given that many of the structural motifs found in biotin-streptavidin are utilized in numerous other protein-ligand interactions, it is very desirable to map out the structural and dynamical motifs underlying the slow dissociation kinetics in this system. Experiments have reported both the binding affinity (K D ) and the binding/unbinding rate constants (k on , k of f respectively, with K D = k on /k of f ) for this system with and without mutations in the host. Of these numbers, the unbinding rate constant k of f (also often represented through its inverse, the residence time) has recently received a lot of attention as possibly being a much better predictor of drug efficacy compared to the static K D . 8-10 While experiments can provide a direct measurement of k of f , it is not so easy to derive from experiments direct information into the molecular determinants of the residence time. These determinants could come from a diverse range -protein-ligand contacts, solvation, protein/ligand flexibilities and many others. Having an atomistic resolution understanding of the role played by these determinants in the unbinding dynamics, one could then propose structural modifications that would assist in rational design of drugs with desired residence times. With the advent of petaflop computing and reliable forc...

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Unbinding Kinetics of a p38 MAP Kinase Type II Inhibitor from Metadynamics Simulations

Cited by 204 publications

References 70 publications

Structure-Unbinding Kinetics Relationship of p38α MAPK Inhibitors

Structure-Unbinding Kinetics Relationship of p38α MAPK Inhibitors

3D Pharmacophore-based Virtual Screening, Docking Approaches toward the Discovery of Novel HPPD Inhibitors

Molecular determinants and bottlenecks in the unbinding dynamics of biotin-streptavidin

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