Metadynamics as a Postprocessing Method for Virtual Screening with Application to the Pseudokinase Domain of JAK2

Cutrona, Kara J.; Newton, Ana S.; Krimmer, S.G.; Tirado‐Rives, Julian; Jorgensen, William

doi:10.1021/acs.jcim.0c00276

Cited by 15 publications

(42 citation statements)

References 65 publications

(130 reference statements)

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“…23 Though it and analogues were predicted to bind strongly to JAK2 JH2 by docking with Glide, 27−29 they exhibited little or no binding to JAK2 JH2 when tested using a fluorescence polarization (FP) assay. 23 JAK198 possesses three of the four pharmacophore elements described above: the hydrogen-bond donor−acceptor−donor motif (Figure 1, magenta), the phenyl ring (Figure 1, green), and the terminal carboxylic acid (Figure 1, blue). The aryl nitrile or sulfonamide moiety is absent in JAK198 and could explain, in part, the poor binding.…”

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confidence: 99%

Conversion of a False Virtual Screen Hit into Selective JAK2 JH2 Domain Binders Using Convergent Design Strategies

Henry

Liosi

Ippolito

et al. 2022

ACS Med. Chem. Lett.

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The Janus kinase 2 (JAK2) pseudokinase domain (JH2) is an ATP-binding domain that regulates the activity of the catalytic tyrosine kinase domain (JH1). Dysregulation of JAK2 JH1 signaling caused by the V617F mutation in JH2 is implicated in various myeloproliferative neoplasms. To explore if JAK2 activity can be modulated by a small molecule binding to the ATP site in JH2, we have developed several ligand series aimed at selectively targeting the JAK2 JH2 domain. We report here the evolution of a false virtual screen hit into a new JAK2 JH2 series. Optimization guided by computational modeling has yielded analogues with nanomolar affinity for the JAK2 JH2 domain and >100-fold selectivity for the JH2 domain over the JH1 domain. A crystal structure for one of the potent compounds bound to JAK2 JH2 clarifies the origins of the strong binding and selectivity. The compounds expand the platform for seeking molecules to regulate JAK2 signaling, including V617F JAK2 hyperactivation.

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confidence: 99%

Conversion of a False Virtual Screen Hit into Selective JAK2 JH2 Domain Binders Using Convergent Design Strategies

Henry

Liosi

Ippolito

et al. 2022

ACS Med. Chem. Lett.

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“…To hunt for the correct binding poses, we used metadynamics (Cutrona et al, 2020 ) to evaluate the docking results. The receptor structure containing 5 crystal water molecules was prepared using Protein Preparation Wizard panel (Sastry et al, 2013 ), including adding hydrogen atoms, removing heteroatoms, and protonation state prediction (pH 7.0).…”

Section: Methodsmentioning

confidence: 99%

Hydrogen bonding penalty used for virtual screening to discover potent inhibitors for Papain‐Like cysteine proteases of SARS‐CoV‐2

et al. 2022

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The Papain‐Like proteases (PLpro) of SARS‐CoV‐2 play a crucial role in viral replication and the formation of nonstructural proteins. To find available inhibitors, the 3D structure of PLpro of SARS2 was obtained by homologous modelling, and we used this structure as a target to search for inhibitors through molecular docking and MM/GBSA binding free energy rescoring. A novel hydrogen bonding penalty was applied to the screening process, which meanwhile took desolvation into account. Finally, 61 compounds were acquired and 4 of them with IC 50 at micromolar level tested in vitro enzyme activity assay, which includes clinical drugs tegaserod. Considering the importance of crystal water molecules, the 4 compounds were re‐docked and considered bound waters in the active site as a part of PLpro. The binding modes of these 4 compounds were further explored with metadynamics simulations. The hits will provide a starting point for future key interactions identified and lead optimization targetting PLpro.

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“…These efforts have led to the development of several series of novel JAK2 JH2 binders: indoloxytriazines, diaminotriazoles, and pyrrolopyrimidines (Figure ). , …”

Section: Introductionmentioning

confidence: 99%

Insights on JAK2 Modulation by Potent, Selective, and Cell-Permeable Pseudokinase-Domain Ligands

et al. 2022

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JAK2 is a non-receptor tyrosine kinase that regulates hematopoiesis through the JAK-STAT pathway. The pseudokinase domain (JH2) is an important regulator of the activity of the kinase domain (JH1). V617F mutation in JH2 has been associated with the pathogenesis of various myeloproliferative neoplasms, but JAK2 JH2 has been poorly explored as a pharmacological target. In light of this, we aimed to develop JAK2 JH2 binders that could selectively target JH2 over JH1 and test their capacity to modulate JAK2 activity in cells. Toward this goal, we optimized a diaminotriazole lead compound into potent, selective, and cell-permeable JH2 binders leveraging computational design, synthesis, binding affinity measurements for the JH1, JH2 WT, and JH2 V617F domains, permeability measurements, crystallography, and cell assays. Optimized diaminotriazoles are capable of inhibiting STAT5 phosphorylation in both WT and V617F JAK2 in cells.

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Metadynamics as a Postprocessing Method for Virtual Screening with Application to the Pseudokinase Domain of JAK2

Cited by 15 publications

References 65 publications

Conversion of a False Virtual Screen Hit into Selective JAK2 JH2 Domain Binders Using Convergent Design Strategies

Conversion of a False Virtual Screen Hit into Selective JAK2 JH2 Domain Binders Using Convergent Design Strategies

Hydrogen bonding penalty used for virtual screening to discover potent inhibitors for Papain‐Like cysteine proteases of SARS‐CoV‐2

Insights on JAK2 Modulation by Potent, Selective, and Cell-Permeable Pseudokinase-Domain Ligands

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