Dataset Information

**Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential V600E-BRAF kinase inhibitors**.

ABSTRACT:

Objectives

V600E-BRAF kinase is an essential therapeutic target in melanoma and other types of tumors. Because of its resistance to known inhibitors and the adverse effects of some identified inhibitors, investigation of new potent inhibitors is necessary.

Methods

In the present work, in silico strategies such as molecular docking simulation, pharmacokinetic evaluation, and density functional theory (DFT) computations were used to identify potential V600E-BRAF inhibitors from a set of 72 anticancer compounds in the PubChem database.

Results

Five top-ranked molecules (12, 15, 30, 31, and 35) with excellent docking scores (MolDock score ≥90 kcal mol^-1, Rerank score ≥60 kcal mol^-1) were selected. Several potential binding interactions were discovered between the molecules and V600E-BRAF. The formation of H-bonds and hydrophobic interactions with essential residues of V600E-BRAF suggested the high stability of these complexes. The selected compounds had excellent pharmacological properties according to the drug likeness rules (bioavailability) and pharmacokinetic properties. Similarly, the energy for the frontier molecular orbitals, such as the HOMO, LUMO, energy gap, and other reactivity parameters, was computed with DFT. The frontier molecular orbital surfaces and electrostatic potentials were investigated to demonstrate the charge-density distributions potentially associated with anticancer activity.

Conclusion

The identified compounds were found to be potent hit compounds for V600E-BRAF inhibition with superior pharmacokinetic properties; therefore, they may be promising cancer drug candidates.

SUBMITTER: Umar AB

PROVIDER: S-EPMC9976450 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

<b>Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential <i>V600E-BRAF</i> kinase</b> <b>inhibitors</b>.

Umar Abdullahi B AB Uzairu Adamu A

Journal of Taibah University Medical Sciences 20230204 5

<h4>Objectives</h4><i>V600E-BRAF</i> kinase is an essential therapeutic target in melanoma and other types of tumors. Because of its resistance to known inhibitors and the adverse effects of some identified inhibitors, investigation of new potent inhibitors is necessary.<h4>Methods</h4>In the present work, in silico strategies such as molecular docking simulation, pharmacokinetic evaluation, and density functional theory (DFT) computations were used to identify potential <i>V600E-BRAF</i> inhibi ...[more]

PMID: 36875340

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Project description:BackgroundMost mutations in melanoma affect one critical amino acid on BRAF gene, resulting in the V600E substitution. Patient management is often based on the use of specific inhibitors targeting this mutation.MethodsDNA and RNA mutation status was assessed in 15 melanoma cell lines by Sanger sequencing and RNA-seq. We tested the cell lines responsiveness to BRAF inhibitors (vemurafenib and PLX4720, BRAF-specific and sorafenib, BRAF non-specific). Cell proliferation was assessed by MTT colorimetric assay. BRAF V600E RNA expression was assessed by qPCR. Expression level of phosphorylated-ERK protein was assessed by Western Blotting as marker of BRAF activation.ResultsThree cell lines were discordant in the mutation detection (BRAF V600E at DNA level/Sanger sequencing and BRAF WT on RNA-seq). We initially postulated that those cell lines may express only the WT allele at the RNA level although mutated at the DNA level. A more careful analysis showed that they express low level of BRAF RNA and the expression may be in favor of the WT allele. We tested whether the discordant cell lines responded differently to BRAF-specific inhibitors. Their proliferation rate decreased after treatment with vemurafenib and PLX4720 but was not affected by sorafenib, suggesting a BRAF V600E biological behavior. Yet, responsiveness to the BRAF specific inhibitors was lower as compared to the control. Western Blot analysis revealed a decreased expression of p-ERK protein in the BRAF V600E control cell line and in the discordant cell lines upon treatment with BRAF-specific inhibitors. The discordant cell lines showed a lower responsiveness to BRAF inhibitors when compared to the BRAF V600E control cell line. The results obtained from the inhibition experiment and molecular analyses were also confirmed in three additional cell lines.ConclusionCell lines carrying V600E mutation at the DNA level may respond differently to BRAF targeted treatment potentially due to a lower V600E RNA expression.

Dataset Information

**Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential V600E-BRAF kinase inhibitors**.

Objectives

Methods

Results

Conclusion

Publications

<b>Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential <i>V600E-BRAF</i> kinase</b> <b>inhibitors</b>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential V600E-BRAF kinase inhibitors.

Objectives

Methods

Results

Conclusion

Publications

<b>Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential <i>V600E-BRAF</i> kinase</b> <b>inhibitors</b>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

**Virtual screening, pharmacokinetic, and DFT studies of anticancer compounds as potential V600E-BRAF kinase inhibitors**.