Elaborate ligand-based modeling and subsequent synthetic exploration unveil new nanomolar Ca2+/calmodulin-dependent protein kinase II inhibitory leads

Shahin, Rand; Taha, Mutasem O.

doi:10.1016/j.bmc.2011.10.071

Cited by 25 publications

(41 citation statements)

References 40 publications

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“…The resulting pharmacophores were validated using receiver operating characteristic (ROC) curve analysis, which evaluates the ability of tested pharmacophore to discriminate active compounds from a list composed of known 50 active ligands, i.e., against the targeted enzyme (i.e., PI3K-γ, Renin, or JAK1, IC 50 ≤ 1.0 μM), and a larger list of decoys (300–750 compounds, IC 50 range from 2 to 10 000 μM). − The testing sets were assembled from CHEMBL database . Details of the ROC analysis are shown in Supporting Information Section SM-2. − ,,,− ,− …”

Section: Methodsmentioning

confidence: 99%

“…A pharmacophore is an abstract description of steric and electronic features necessary to be present in a particular ligand to allow optimal recognition and binding to a specific receptor and to trigger subsequent biological function. − Pharmacophore models are derived either by structure-based or ligand-based approaches. − In structure-based methodologies, pharmacophore models are extracted from crystallographic complexes involving high affinity ligands cocrystallized within targeted proteins . However, despite ligand–receptor binding involving numerous attractive interactions, only a few can be defined as pharmacophoric, i.e., critical for complex stability. − …”

Section: Introductionmentioning

confidence: 99%

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Combining Stochastic Deformation/Relaxation and Intermolecular Contacts Analysis for Extracting Pharmacophores from Ligand–Receptor Complexes

Hatmal

Taha

2018

J. Chem. Inf. Model.

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We previously combined molecular dynamics (classical or simulated annealing) with ligand-receptor contacts analysis as a means to extract valid pharmacophore model(s) from single ligand-receptor complexes. However, molecular dynamics methods are computationally expensive and time-consuming. Here we describe a novel method for extracting valid pharmacophore model(s) from a single crystallographic structure within a reasonable time scale. The new method is based on ligand-receptor contacts analysis following energy relaxation of a predetermined set of randomly deformed complexes generated from the targeted crystallographic structure. Ligand-receptor contacts maintained across many deformed/relaxed structures are assumed to be critical and used to guide pharmacophore development. This methodology was implemented to develop valid pharmacophore models for PI3K-γ, RENIN, and JAK1. The resulting pharmacophore models were validated by receiver operating characteristic (ROC) analysis against inhibitors extracted from the CHEMBL database. Additionally, we implemented pharmacophores extracted from PI3K-γ to search for new inhibitors from the National Cancer Institute list of compounds. The process culminated in new PI3K-γ/mTOR inhibitory leads of low micromolar ICs.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combining Stochastic Deformation/Relaxation and Intermolecular Contacts Analysis for Extracting Pharmacophores from Ligand–Receptor Complexes

Hatmal

Taha

2018

J. Chem. Inf. Model.

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“…[43] The most chemically similar compound is an inhibitor of CaMKIId that was discovered using pharmacophore search, which features as imilar quinazoline core as compound 1 (ECFP4 fingerprints, Ta nimoto coefficient of 0.154). [45] In their compound, the alkene linker of the benzene substituent is shortened with as econdary amine, and the alkylamine tail of 1 is replaced with am ethylpiperidine group. Additionally,w e compared the structure of 1 against~55 000 compounds in ChEMBL'sK inase SARfarid atabase.…”

Section: Virtual Screening Identifies Active Compoundsmentioning

confidence: 99%

Structure‐Based Target‐Specific Screening Leads to Small‐Molecule CaMKII Inhibitors

Zhou

et al. 2017

ChemMedChem

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Target-specific scoring methods are more commonly used to identify small-molecule inhibitors among compounds docked to a target of interest. Top candidates that emerge from these methods have rarely been tested for activity and specificity across a family of proteins. Here, we dock a chemical library to CaMKIIδ, a member of the Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) family, and rescore the resulting protein-compound structures using SVMSP, a target-specific method that we previously developed. Among the 35 selected candidates, three hits were identified, such as quinazoline compound 1 (KIN-1), which inhibited CaMKIIδ kinase activity with single-digit micromolar IC50. Activity across the kinome was assessed by profiling analogs of 1, namely 6 (KIN-236), and an analog of hit compound 2 (KIN-15), namely 14 (KIN-332), against 337 kinases. Interestingly, for 6 (KIN-236), CaMKIIδ and homolog CaMKIIγ were among the top 10 targets. Among the top 25 targets of 6 (KIN-236), IC50 values ranged from 5 to 22 μM. Compound 14 (KIN-332) was not specific towards CaMKII kinases, but the compound inhibited two kinases with sub-micromolar IC50s among the top 25. Derivatives of 1 were tested against several kinases including several members of the CaMK family. The data afforded a limited structure-activity relationship study. Molecular dynamics simulations with explicit-solvent followed by end-point MM-GBSA free energy calculations revealed strong engagement of specific residues within the ATP-binding pocket, and also changes in the dynamics as a result of binding. This work suggests that target-specific scoring approaches like SVMSP may hold promise for the identification of small-molecule kinase inhibitors that exhibit some level of specificity towards the target of interest across a large number of proteins.

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“…Virtual screening methodologies are broadly used nowadays to find novel specific kinase inhibitors. Specifically, ligand-based 3D pharmacophores were developed for CaMK-IIδ by Shahin and Taha in 2011 [ 29 ]. This study embraced the use of multiple linear regressions and genetic function algorithm in order to build a predictive quantitative structure–activity relationship equation that can describe the activity of potent CaMK-IIδ inhibitors [ 30 ].…”

Section: Camk-iiδmentioning

confidence: 99%

“…Specifically, ligand-based 3D pharmacophores were developed for CaMK-IIδ by Shahin and Taha in 2011 [ 29 ]. This study embraced the use of multiple linear regressions and genetic function algorithm in order to build a predictive quantitative structure–activity relationship equation that can describe the activity of potent CaMK-IIδ inhibitors [ 30 ]. Finally, this approach resulted in several active inhibitors ranging in their activity from 0.02 to 2.46 µM (see compounds 11 and 12 , Table 1 ) [ 29 ].…”

Section: Camk-iiδmentioning

confidence: 99%

Research Advances in Kinase Enzymes and Inhibitors for Cardiovascular Disease Treatment

et al. 2017

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The targeting of protein kinases has great future potential for the design of new drugs against cardiovascular diseases (CVDs). Enormous efforts have been made toward achieving this aim. Unfortunately, kinase inhibitors designed to treat CVDs have suffered from numerous limitations such as poor selectivity, bad permeability and toxicity. So, where are we now in terms of discovering effective kinase targeting drugs to treat CVDs? Various drug design techniques have been approached for this purpose since the discovery of the inhibitory activity of Staurosporine against protein kinase C in 1986. This review aims to provide context for the status of several emerging classes of direct kinase modulators to treat CVDs and discuss challenges that are preventing scientists from finding new kinase drugs to treat heart disease.

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Elaborate ligand-based modeling and subsequent synthetic exploration unveil new nanomolar Ca2+/calmodulin-dependent protein kinase II inhibitory leads

Cited by 25 publications

References 40 publications

Combining Stochastic Deformation/Relaxation and Intermolecular Contacts Analysis for Extracting Pharmacophores from Ligand–Receptor Complexes

Combining Stochastic Deformation/Relaxation and Intermolecular Contacts Analysis for Extracting Pharmacophores from Ligand–Receptor Complexes

Structure‐Based Target‐Specific Screening Leads to Small‐Molecule CaMKII Inhibitors

Research Advances in Kinase Enzymes and Inhibitors for Cardiovascular Disease Treatment

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