Selection of Best Crystal Structure for Initiating Docking-Based Virtual Screening Studies of Cdk2 Inhibitors: A Cross-Docking and Dud Set Validation Approach

Joshi, Akshada; Bhojwani, Heena R.; Joshi, Urmila J.

doi:10.53879/id.56.06.11592

Cited by 2 publications

(2 citation statements)

References 41 publications

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“…Our previous work on the selecting of the most suitable crystal structure for docking into CDK2 receptor had indicated that 2WXV is the most suitable crystal structure for docking of chemically diverse ligands. This prompted us to use this crystal structure for docking of CDK2 inhibitors [31]. The docking protocol was validated by calculating RMSD values between the docked conformation of the inhibitor and native conformation.…”

Section: Cdk2 and Egfr Kinase Inhibition By Adp Glo Tm Assaymentioning

confidence: 99%

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Cinnamamide-chalcone derivatives as CDK2 inhibitors: synthesis, pharmacological evaluation, and molecular modelling study

Joshi¹,

Bhojwani²,

Joshi³

et al. 2022

J IRAN CHEM SOC

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A series of 13 novel cinnamamide-chalcone derivatives (2a-2m) were synthesized and evaluated for their antiproliferative activity against MCF-7, K562, U373MG, and HT-29 cell lines by SRB assay. Considering the activities on MCF-7 cell line, eight compounds were tested for the in-vitro CDK2 inhibition and four (2g, 2h, 2k and 2l) were found to possess good activity (IC 50 <10µM). These four compounds were tested on EGFR kinase to assess the selectivity towards CDK2 and were found be nearly two times more selective.To corroborate the in-vitro enzyme assay data with binding, the compounds were docked into the CDK2 and EGFR using Glide software. The docking studies reveal that all eight compounds form hydrogen bonds with Lys33 (β-3 region) and Leu83 (hinge region) in CDK2 and the docking scores correlate well with the IC 50 values. The most active compounds on CDK2 when docked in EGFR had lower docking scores. Only one compound interacts with Lys721 (β-3 region) and Met769 (hinge region). The stability of interactions with CDK2 was assessed for 2k and 2l by molecular dynamics simulation using Desmond software. In conclusion, three compounds possess excellent activity against MCF-7 cell line and good activity against CDK2.

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Section: Cdk2 and Egfr Kinase Inhibition By Adp Glo Tm Assaymentioning

confidence: 99%

“…The crystal structure used for the studies were downloaded from protein data bank. These included PDB 2WXV for CDK2 [31] and PDB 1M17 for EGFR [48,49]. These are complexed with inhibitor with ligand identi er WXV and AQ4; respectively.…”

Section: Molecular Dockingmentioning

confidence: 99%

Cinnamamide-chalcone derivatives as CDK2 inhibitors: synthesis, pharmacological evaluation, and molecular modelling study

Joshi¹,

Bhojwani²,

Joshi³

et al. 2022

J IRAN CHEM SOC

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Evaluation of Benzamide-Chalcone Derivatives as EGFR/CDK2 Inhibitor: Synthesis, In-Vitro Inhibition, and Molecular Modeling Studies

Joshi¹,

Bhojwani²,

Wagal³

et al. 2022

ACAMC

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Background: EGFR (Epidermal Growth Factor Receptor) and CDK2 (Cyclin Dependent Kinase 2) are important targets in the treatment of many solid tumors and different ligands of these receptors share many common structural features. Objective: The study involved synthesis of benzamide-substituted chalcones and determination of their antiproliferative activity as well as preliminary evaluation of EGFR and CDK2 inhibitory potential using both receptor binding and computational methods. Methods: We synthesized 13 benzamide-substituted chalcone derivatives and tested their antiproliferative activity against MCF-7, HT-29 and U373MG cell-lines using Sulforhodamine B Assay. Four compounds were examined for activity against EGFR and CDK2 kinase. The compounds were docked into both EGFR and CDK2 using Glide software. The stability of the interactions for most active compound was evaluated by Molecular Dynamics Simulation using Desmond software. Molecular Docking studies on mutant EGFR (T790M, T790M/L858R, and T790M/C797S) were also carried out. Results: From the SRB assay, we concluded that compounds 1g, and 1k were effective in inhibiting the growth of MCF-7 cell line whereas the other compounds were moderately active. Most compounds were either moderately active or inactive on U373 MG and HT-29 cell line. Compounds 1g and 1k showed good inhibitory activity against CDK2 kinase while 1d and 1f were moderately active. Compounds 1d, 1f, 1g, and 1k were moderately active against EGFR kinase. Molecular docking reveals involvement of one hydrogen bond with Met793 in binding with EGFR however; it was not stable during simulation and these compounds bind to the receptor mainly via hydrophobic contacts. This fact also points towards a different orientation of the inhibitor within the active site of EGFR kinase. Binding mode analysis for CDK2 inhibition studies indicate that hydrogen bonding interaction with Lys 33 and Leu83 are important for the activity. These interactions were found to be stable throughout the simulation. Considering the results for wild-type EGFR inhibition, the docking studies on mutants were performed and which indicate that the compounds bind to the mutant EGFR but the amino acid residues involved are similar to the wild-type EGFR and therefore, the selectivity seems to be limited. Conclusion: These benzamide-substituted chalcone derivatives will be useful as lead molecules for the further development of newer inhibitors of EGFR and/or CDK2 kinases.

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Selection of Best Crystal Structure for Initiating Docking-Based Virtual Screening Studies of Cdk2 Inhibitors: A Cross-Docking and Dud Set Validation Approach

Cited by 2 publications

References 41 publications

Cinnamamide-chalcone derivatives as CDK2 inhibitors: synthesis, pharmacological evaluation, and molecular modelling study

Cinnamamide-chalcone derivatives as CDK2 inhibitors: synthesis, pharmacological evaluation, and molecular modelling study

Evaluation of Benzamide-Chalcone Derivatives as EGFR/CDK2 Inhibitor: Synthesis, In-Vitro Inhibition, and Molecular Modeling Studies

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