Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors

Bennett, Michael J.; Wu, Yinbing; Boloor, Amogh; Matuszkiewicz, Jennifer; O’Connell, Shawn M.; Shi, Leming; Stansfield, Ryan; Rosario, Joselyn R. Del; Veal, James M.; Hosfield, David J.; Xu, Jingjing; Kaldor, Stephen W.; Stafford, Jackie; Betancort, Juan M.

doi:10.1016/j.bmcl.2018.04.016

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which is a target related to cancer and other diseases. We applied the EC scores to two literature-reported BRD4 inhibitor sets , and identified no correlation between EC scores and bioactivity. We then applied esp_extre and sas_ratio to select the ligands suitable for using the EC score for ranking.…”

Section: Resultsmentioning

confidence: 99%

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Modified Electrostatic Complementary Score Function and Its Application Boundary Exploration in Drug Design

Zhao

Wang

et al. 2022

J. Chem. Inf. Model.

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In recent years, machine learning (ML) models have been found to quickly predict various molecular properties with accuracy comparable to high-level quantum chemistry methods. One such example is the calculation of electrostatic potential (ESP). Different ESP prediction ML models were proposed to generate surface molecular charge distribution. Electrostatic complementarity (EC) can apply ESP data to quantify the complementarity between a ligand and its binding pocket, leading to the potential to increase the efficiency of drug design. However, there is not much research discussing EC score functions and their applicability domain. We propose a new EC score function modified from the one originally developed by Bauer and Mackey, and confirm its effectiveness against the available Pearson’s R correlation coefficient. Additionally, the applicability domain of the EC score and two indices used to define the EC score application scope will be discussed.

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Section: Resultsmentioning

confidence: 99%

“…In the first series of compounds (Figure 10), 21 we retrieved their 3D complex (PDB id 6CKR) and two indices, and the EC scores are calculated in Table S5. It is evident that ligands 44, 47, 49, 50, 52, and 54 meet the criteria that esp_extre is larger than 20 kcal/(mol*e) and sas_ratio is smaller than 0.35.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Modified Electrostatic Complementary Score Function and Its Application Boundary Exploration in Drug Design

Zhao

Wang

et al. 2022

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which is a target related to cancer and other diseases. We applied the EC scores to two literatures reported BRD4 inhibitor sets 21,22 and identified no correlation between EC scores and bioactivity. We then applied esp_extre and sas_ratio to select the ligands suitable to use EC score for ranking.…”

Section: Figure 5 Relationship Between New Ec Scores (Left) and Pears...mentioning

confidence: 99%

“…We then applied esp_extre and sas_ratio to select the ligands suitable to use EC score for ranking. In the first series of compounds (Figure 10), 21 we retrieved their 3D complex (PDB id 6CKR)…”

Section: Figure 5 Relationship Between New Ec Scores (Left) and Pears...mentioning

confidence: 99%

A Modified Electrostatic Complementary Score Function and Its Application Boundary Exploration in Drug Design

Zhao¹,

Wang²,

Zhang³

2022

Preprint

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In recent years, machine learning (ML) models have been found to quickly predict various molecular properties with accuracy comparable to high level quantum chemistry methods. One such example is the calculation of electrostatic potential (ESP). Different ESP prediction ML models were proposed to generate surface molecular charge distribution. Electrostatic complementarity (EC) can quantitatively apply ESP data to scale the complementarity between a ligand and its binding pocket, leading to the potential to increase efficiency of drug design. However, there is not much research discussing EC score functions and its application boundary. We propose a new EC score function modified from the one originally developed by Bauer and Mackey, and confirmed its effectiveness against the available Pearson’s R correlation coefficient. Additionally, the application boundary of the EC score and two indices used to define the EC score application scope will be discussed.

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“…Specifically, Trotabresib was modified with a 1,2,3-triazole functional group at the position-6 of the isoquinolone ring to enable late-stage installation of fluorine-18 (similar 1,2-diazole derivatives of Trotabresib at this position have also been found to be potent inhibitors of BET proteins). 16…”

mentioning

confidence: 99%

Bromodomain and extraterminal protein-targeted probe enables tumour visualisation in vivo using positron emission tomography

et al. 2023

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Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors

Cited by 9 publications

References 28 publications

Modified Electrostatic Complementary Score Function and Its Application Boundary Exploration in Drug Design

Modified Electrostatic Complementary Score Function and Its Application Boundary Exploration in Drug Design

A Modified Electrostatic Complementary Score Function and Its Application Boundary Exploration in Drug Design

Bromodomain and extraterminal protein-targeted probe enables tumour visualisation in vivo using positron emission tomography

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