A QM/MM study of the binding of RAPTA ligands to cathepsin B

Ciancetta, Antonella; Genheden, Samuel; Ryde, Ulf

doi:10.1007/s10822-011-9448-7

Cited by 37 publications

(40 citation statements)

References 77 publications

(97 reference statements)

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“…Therefore, the relative energy results from the QM/MM‐PBSA calculations using both the docking poses directly and the QM/MM relaxed poses (rigid receptor) are qualitatively consistent. QM/MM‐PBSA and MM‐PB(GB)SA are recognized for their accuracy in prediction of relative binding affinities (51–53), which is sufficient for most applications. On the contrary, the absolute energy values are too negative, but this is also a problem with the parent MM‐PB(GB)SA methodology (55) and is due to the approximations applied and inherent in these methods.…”

Section: Resultsmentioning

confidence: 99%

3′‐Axial CH₂OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why

et al. 2012

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Glycogen phosphorylase is a molecular target for the design of potential hypoglycemic agents. Structure-based design pinpointed that the 3¢-position of glucopyranose equipped with a suitable group has the potential to form interactions with enzyme's cofactor, pyridoxal 5¢-phosphate (PLP), thus enhancing the inhibitory potency. Hence, we have investigated the binding of two ligands, 1-(b-D-glucopyranosyl)5-fluorouracil (GlcFU) and its 3¢-CH 2 OH glucopyranose derivative. Both ligands were found to be low micromolar inhibitors with K i values of 7.9 and 27.1 lM, respectively. X-ray crystallography revealed that the 3¢-CH 2 OH glucopyranose substituent is indeed involved in additional molecular interactions with the PLP c-phosphate compared with GlcFU. However, it is 3.4 times less potent. To elucidate this discovery, docking followed by postdocking Quantum Mechanics/Molecular Mechanics-Poisson-Boltz-mann Surface Area (QM ⁄ MM-PBSA) binding affinity calculations were performed. While the docking predictions failed to reflect the kinetic results, the QM/MM-PBSA revealed that the desol-vation energy cost for binding of the 3¢-CH 2 OH-substituted glucopyranose derivative outweigh the enthalpy gains from the extra contacts formed. The benefits of performing postdocking calculations employing a more accurate solvation model and the QM/MM-PBSA methodology in lead optimization are therefore highlighted, specifically when the role of a highly polar ⁄ charged binding interface is significant. Glycogen phosphorylase (GP) is a key enzyme in glycogen metabolism that catalyzes the first step in the intracellular degradation of glycogen (1). A large number of compounds have been reported to bind at five distinct binding sites (1-3): the catalytic, the allosteric, the new allosteric, the inhibitor and the glycogen storage site. The efficacy of such inhibitors on blood glucose control and hepatic gly-cogen balance has been confirmed from animal studies and in vitro cell biology experiments (4-8) validating GP as an important target for structure-based inhibitor design of new hypoglycemic agents for the treatment of diabetes type 2. Furthermore, the number of patents filed by pharmaceutical and biotechnology companies targeting GP for the discovery of novel hypoglycemic agents has been steadily increasing in the last 3 years (9). Recently, we have investigated the binding of a series of 3¢-fluori-nated pyrimidine glucopyranonucleosides to GP which proved to be medium potency inhibitors with IC 50 values ranging between 6.5 mM and 46.4 lM (10). All the 3¢-glucose substituents were in the 3¢-equatorial position. The 3¢ carbon of glucose is 5 away from the c-phosphate of pyridoxal 5¢-phosphate (PLP) in the GPb-aD glucose complex (11), in the direction of the 3¢-axial position. Suitable sub-stituents at the 3¢-axial position have therefore the potential to form interactions with the proximal PLP c-phosphate (a mono-anion). Thus, building on our previous studies of modified nucleosides (10), we report here the synthesis, biochemical e...

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Section: Resultsmentioning

confidence: 99%

3′‐Axial CH₂OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why

et al. 2012

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“…Burger et al [23] reported that a short molecular dynamics simulation on the docked ligand pose followed by QM/MM optimization drastically improves both the prediction of native binding poses and the correlation between experimental and computed binding free energy. Ciancetta et al [27] studied the binding of a series of six Ru(II)-arene PTA (RAPTA) ligands to catB using a QM/MM approach with Poisson Boltzmann surface area (PBSA) to implicitly model solvation of the protein-ligand system. QM calculations were performed at the DFT level.…”

Section: Qm and Qm/mm Methods For Improving The Scoring Process In Domentioning

confidence: 99%

Induced fit docking, and the use of QM/MM methods in docking

Lill

2013

Drug Discovery Today: Technologies

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Docking methods are popular computational techniques in drug discovery to identify new active molecules that bind to a given biological target. Although widely used, the predictive reliability of docking methods is often limited by the inability to accurately and efficiently model protein flexibility and quantify binding strength. We highlight several emerging concepts that address those methodological issues including a discussion on the incorporation of QM/MM methodologies in the scoring process.

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“…Despite the high number of in vitro, in vivo, and theoretical studies on the behavior of the RAPTA-based compounds, their mechanism of action is not well known (Ciancetta et al 2011) and this limits further development. The poor correlation between the binding of RAPTA compounds to DNA and their cytotoxicity suggested that these compounds act through a different mechanism from the classical platinum anticancer agents (Ciancetta et al 2011).…”

Section: Inherent Advantages Of Ru-based Anticancer Complexesmentioning

confidence: 99%

“…The poor correlation between the binding of RAPTA compounds to DNA and their cytotoxicity suggested that these compounds act through a different mechanism from the classical platinum anticancer agents (Ciancetta et al 2011). The mechanisms of action of Ru-based anticancer compounds are comparatively yet to be explored.…”

Section: Inherent Advantages Of Ru-based Anticancer Complexesmentioning

confidence: 99%

“…The hydrolysis of cisplatin has been shown to be rate constants of 7.56 × 10 -5 and 6.32 × 10 -5 s -1 for the first and second chloride ligands, respectively (Wang et al 2005a). Among emerging new classes of Ru-based anticancer agents are Ru(III) complexes, such as transRu(imidazole) 2 Cl 4 and trans-Ru(DMSO)(imidazole)Cl 4 as antimetastatic agents (Ciancetta et al 2011). …”

Section: Introductionmentioning

confidence: 99%

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Development of ruthenium-based complexes as anticancer agents: toward a rational design of alternative receptor targets

Adeniyi

Ajibade

2016

Reviews in Inorganic Chemistry

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AbstractIn the search for novel anticancer agents, the development of metal-based complexes that could serve as alternatives to cisplatin and its derivatives has received considerable attention in recent years. This becomes necessary because, at present, cisplatin and its derivatives are the only coordination complexes being used as anticancer agents in spite of inherent serious side effects and their limitation against metastasized platinum-resistant cancer cells. Although many metal ions have been considered as possible alternatives to cisplatin, the most promising are ruthenium (Ru) complexes and two Ru compounds, KP1019 and NAMI-A, which are currently in phase II clinical trials. The major obstacle against the rational design of these compounds is the fact that their mode of action in relation to their therapeutic activities and selectivity is not fully understood. There is an urgent need to develop novel metal-based anticancer agents, especially Ru-based compounds, with known mechanism of actions, probable targets, and pharmacodynamic activity. In this paper, we review the current efforts in developing metal-based anticancer agents based on promising Ru complexes and the development of compounds targeting receptors and then examine the future prospects.

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A QM/MM study of the binding of RAPTA ligands to cathepsin B

Cited by 37 publications

References 77 publications

3′‐Axial CH₂OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why

3′‐Axial CH₂OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why

Induced fit docking, and the use of QM/MM methods in docking

Development of ruthenium-based complexes as anticancer agents: toward a rational design of alternative receptor targets

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A QM/MM study of the binding of RAPTA ligands to cathepsin B

Cited by 37 publications

References 77 publications

3′‐Axial CH2OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why

3′‐Axial CH2OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why

Induced fit docking, and the use of QM/MM methods in docking

Development of ruthenium-based complexes as anticancer agents: toward a rational design of alternative receptor targets

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Product

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3′‐Axial CH₂OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why

3′‐Axial CH₂OH Substitution on Glucopyranose does not Increase Glycogen Phosphorylase Inhibitory Potency. QM/MM‐PBSA Calculations Suggest Why