Characterization of compound 584, an Abl kinase inhibitor with lasting effects

Puttini, Miriam; Moretti, Loris; Brussolo, Stefania; Gunby, Rosalind H.; Mologni, Luca; Marchesi, Edoardo; Cleris, Loredana; Donella‐Deana, Arianna; Drueckes, Peter; Sala, Elisa; Lucchini, Vittorio; Kubbutat, Michael H.G.; Formelli, Franca; Zambon, Alfonso; Scapozza, Léonardo; Gambacorti‐Passerini, Carlo

doi:10.3324/haematol.12212

Cited by 10 publications

(6 citation statements)

References 37 publications

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“…The computed binding free energy difference is −2.8 ± 0.2 kcal/mol, favoring the new ligand. This is in close agreement with the experimental value, −2.8 kcal/mol 51…”

Section: Resultssupporting

confidence: 92%

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A molecular mechanics model for imatinib and imatinib:kinase binding

Aleksandrov

Simonson

2009

J Comput Chem

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Imatinib is an important anticancer drug, which binds specifically to the Abl kinase and blocks its signalling activity. To model imatinib:protein interactions, we have developed a molecular mechanics force field for imatinib and four close analogues, which is consistent with the CHARMM force field for proteins and nucleic acids. Atomic charges and Lennard-Jones parameters were derived from a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule interacting with imatinib fragments at 32 different positions. We considered both a neutral and a protonated imatinib. The final RMS deviation between the ab initio and force field energies, averaged over both forms, was 0.2 kcal/mol. The model also reproduces the ab initio geometry and flexibility of imatinib. To apply the force field to imatinib:Abl simulations, it is also necessary to determine the most likely imatinib protonation state when it binds to Abl. This was done using molecular dynamics free energy simulations, where imatinib is reversibly protonated during a series of MD simulations, both in solution and in complex with Abl. The simulations indicate that imatinib binds to Abl in its protonated, positively-charged form. To help test the force field and the protonation prediction, we did MD free energy simulations that compare the Abl binding affinities of two imatinib analogs, obtaining good agreement with experiment. Finally, two new imatinib variants were considered, one of which is predicted to have improved Abl binding. This variant could be of interest as a potential drug.

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“…The computed binding free energy difference is −2.8 ± 0.2 kcal/mol, favoring the new ligand. This is in close agreement with the experimental value, −2.8 kcal/mol 51…”

Section: Resultssupporting

confidence: 92%

“…In the second variant, “R1Cl,” chloride replaces the hydrogen in the C28H group 50, 51. This group binds in a hydrophobic pocket formed by residues Ile293, Leu298, Leu354, His361, and Val3799; see Figure 9.…”

Section: Resultsmentioning

confidence: 99%

A molecular mechanics model for imatinib and imatinib:kinase binding

Aleksandrov

Simonson

2009

J Comput Chem

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“…2) and with~2 0-300-fold greater cellular activity in vitro and in vivo than imatinib, which was attributed to a slower off-rate. [17] To our knowledge, this represented the first evidence of higher anti-Abl activity potentially caused by a slower off-rate emphasising the importance of understanding binding kinetics in drug discovery. [18] Studies of binding kinetics are now implemented in the process of the hit to lead optimization and to develop quantitative structure kinetics relationships (QSKR).…”

Section: Binding Kinetics Of Protein Kinase Inhibitors Make the Diffementioning

confidence: 88%

The Pharmaceutical Biochemistry Group: Where Pharmaceutical Chemistry Meets Biology and Drug Delivery

Perozzo¹,

Scapozza²

2012

Chimia

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Successful drug discovery and development of new therapeutics is a long, expensive multidisciplinary process needing innovation and the integration of smart cutting edge science and technology to overcome the challenges in taking a drug from the bench to the bedside. The research activities of the Pharmaceutical Biochemistry group span the drug discovery and development process, providing an interface that brings together pharmaceutical chemistry, biochemistry, structural biology, computational chemistry and biopharmaceutics. Formulation and drug delivery are brought into play at an earlier stage when facing the perennial challenge of transforming a potent molecule in vitro into a therapeutic agent in vivo. Concomitantly, drug delivery results can be understood at a molecular level. This broad range of interdisciplinary research activities and competences enables us to address key challenges in modern drug discovery and development, provides a powerful collaborative platform for other universities and the pharmaceutical industry and an excellent training platform for pharmacists and pharmaceutical scientists who will later be involved in drug discovery and development.

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“…A correlation of in vivo efficacy with residence time has already been demonstrated for selected GPCRs, such as CCR5 [8], the β-2-adrenergic receptor [9], and the A 2A adenosine receptor [10]. In the kinase family, the dual tyrosine kinase inhibitor Lapatinib showed a long residence time that could be correlated with efficacy [11]. Another example is the ABL inhibitor Nilotinib [12].…”

Section: Introductionmentioning

confidence: 95%

Kinetics for Drug Discovery: an industry-driven effort to target drug residence time

Schuetz

Witte

Wong

et al. 2017

Drug Discovery Today

188

183

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A considerable number of approved drugs show non-equilibrium binding characteristics, emphasizing the potential role of drug residence times for in vivo efficacy. Therefore, a detailed understanding of the kinetics of association and dissociation of a target-ligand complex might provide crucial insight into the molecular mechanism-of-action of a compound. This deeper understanding will help to improve decision making in drug discovery, thus leading to a better selection of interesting compounds to be profiled further. In this review, we highlight the contributions of the Kinetics for Drug Discovery (K4DD) Consortium, which targets major open questions related to binding kinetics in an industry-driven public-private partnership.

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Characterization of compound 584, an Abl kinase inhibitor with lasting effects

Cited by 10 publications

References 37 publications

A molecular mechanics model for imatinib and imatinib:kinase binding

A molecular mechanics model for imatinib and imatinib:kinase binding

The Pharmaceutical Biochemistry Group: Where Pharmaceutical Chemistry Meets Biology and Drug Delivery

Kinetics for Drug Discovery: an industry-driven effort to target drug residence time

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