Computational investigation of novel pyrimidine derivatives as potent FAK inhibitors<i>via</i>3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis

El Bahi, Salma; Boutalaka, Meryem; El Alaouy, Moulay Ahfid; Bouamrane, Soukaina; Alaqarbeh, Marwa; Choukrad, M’barek; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

doi:10.1039/d3nj02471g

Cited by 4 publications

(1 citation statement)

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“…Many pyrimidine analogues have been shown to stop the cell cycle at the G2-M phase, cause significant apoptosis in HepG-2, HCT-116, and MCF-7 cells, and increase caspase-3 levels in HepG-2 cells by 6.5 times compared with the control [19]. Moreover, docking tests were carried out to clarify the binding affinities of the various pyrimidine derivatives that were produced against particular targets [20][21][22]. Additionally, pyrimidine and BOD-IPY were combined to create a specific sort of fluorescent probe that has been developed on multiple occasions.…”

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confidence: 99%

Synthesis, photophysical properties, anticancer evaluation, and molecular docking studies of new pyrimidine linked 4‐arylidene‐thiazolidin‐4‐ones as potent anticancer agents

Jame

2024

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The reaction of 4‐(chloroacetamido)pyrimidine (1) with ammonium thiocyanate gave 2‐(pyrimidin‐4‐ylimino)thiazolidin‐4‐one (2), which, when condensed with four substituted benzaldehyde analogues, gave the consequent 5‐arylidine‐2‐(pyrimidin‐4‐ylimino)thiazolidin‐4‐ones 3a–d. In addition, the absorbance and fluorescence behaviours of pyrimidinylimino‐thiazolidin‐4‐one hybrids 3a–d in various organic solvents were investigated. The emphasis was on studying UV absorption capacities and the effect of various structural components on photophysical qualities such as the 5‐arylidene‐2‐(pyrimidin‐4‐ylimino)thiazolidin‐4‐ones and N,N‐dimethylamino tail. The cytotoxic effect of four pyrimidinylimino‐thiazolidin‐4‐one hybrids 3a–d on tumour cell lines (HepG2, HCT‐116, PC3, MCF‐7) and a normal cell line (WI38) is investigated in this work. The cytotoxicity was measured by comparing the half‐maximal inhibitory concentration (IC50) to the reference medication, 5‐fluorouracil. The findings indicate that these hybrid compounds had varying cytotoxic effects on the cell lines examined; hybrids 3b and 3c demonstrated significant anticancer activity against MCF‐7 with IC50 values of 7.53 ± 0.43 and 9.17 ± 0.31 μM, respectively. The inhibitory efficacy of various synthesized hybrids on the epidermal growth factor receptor (EGFR) kinase was investigated. EGFR is a crucial target in cancer treatment because inhibiting it may reduce tumour development and proliferation. The IC50 value was used to calculate the inhibitory activity, which is the concentration of inhibitor necessary to induce half‐maximal inhibition of EGFR kinase activity. In addition, the predicted ADME results show that pyrimidinylimino‐thiazolidin‐4‐one hybrids have good pharmacokinetic properties; hybrid 3d is more lipophilic than the other compounds. It has a medium molecular weight, a small number of hydrogen bond acceptors and donors, and a large number of aromatic heavy atoms. Moreover, molecular docking simulations revealed precise information on the interactions of pyrimidinylimino‐thiazolidin‐4‐one hybrids 3a–d and 5‐Fu with their respective protein targets. These interactions point to possible pathways for their biological activities and call for more testing to establish their effectiveness as bioactive molecules or therapeutic candidates.

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Section: Introductionmentioning

confidence: 99%

Synthesis, photophysical properties, anticancer evaluation, and molecular docking studies of new pyrimidine linked 4‐arylidene‐thiazolidin‐4‐ones as potent anticancer agents

Jame

2024

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Discovery of a New Isatin Scaffold for BCR‐ABL Tyrosine Kinase Inhibitors Using a Comprehensive Computational Approach

EL Mchichi,

Alaqarbeh,

Lakhlifi

et al. 2024

ChemistrySelect

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Inserting Isatin (1H indole 2,3‐dione) stands out as an exceptionally captivating element in the realm of drug design and development. Hence, there has been a notable focus in numerous anticancer studies on investigating the potential of various derivatives of Isatin (1H indole 2,3‐dione), including imines, hydrazones, thiosemicarbazones, and other compounds. Therefore, to develop new compounds with anticipated high activity, a novel series of 40 Isatin derivatives have undergone 3D‐QSAR studies as potent anticancer agents against the leukemia cell line (K562). This approach has been pursued due to the significant importance placed on exploring the potential of these derivatives. Through the analysis of graphical contour maps, the generated models yielded favorable statistical outcomes and provided valuable insights into the structural elements that exert a significant influence on the activity. Furthermore, both CoMFA and CoMSIA models have shown suitable reliabilities (q2 = 0.689, 0.772, respectively) and predictive abilities (r2pred = 0.780, 0.892, respectively). As a result, the design of five new compounds (T1–T5) based on the Isatin moiety, which exhibited remarkable inhibitory activity, has successfully been accomplished. Accordingly, molecular docking and molecular dynamics (MD) simulations of 100 ns have been utilized to examine the interaction mechanism and conformational changes of the newly designed compounds at the binding site of BCR‐ABL tyrosine kinase. MD simulation revealed that both compounds T1 and T2 formed stable complexes with BCR‐ABL. Additionally, the assessment of the in‐silico pharmacokinetic parameters indicates favorable ADMET properties. These findings hold promise for the future development of potent BCR‐ABL tyrosine kinase inhibitors.

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Structure-odor relationship in pyrazines and derivatives: A physicochemical study using 3D-QSPR, HQSPR, Monte Carlo, molecular docking, ADME-Tox and molecular dynamics

OUABANE,

TABTI,

HAJJI

et al. 2023

Arabian Journal of Chemistry

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Computational investigation of novel pyrimidine derivatives as potent FAK inhibitorsvia3D-QSAR, molecular docking, molecular dynamics simulation and retrosynthesis

Abstract: Focal adhesion kinase is upregulated in various types of cancer and has become an important research target for the development of more effective anticancer drugs.

Cited by 4 publications

References 56 publications

Synthesis, photophysical properties, anticancer evaluation, and molecular docking studies of new pyrimidine linked 4‐arylidene‐thiazolidin‐4‐ones as potent anticancer agents

Synthesis, photophysical properties, anticancer evaluation, and molecular docking studies of new pyrimidine linked 4‐arylidene‐thiazolidin‐4‐ones as potent anticancer agents

Discovery of a New Isatin Scaffold for BCR‐ABL Tyrosine Kinase Inhibitors Using a Comprehensive Computational Approach

Structure-odor relationship in pyrazines and derivatives: A physicochemical study using 3D-QSPR, HQSPR, Monte Carlo, molecular docking, ADME-Tox and molecular dynamics

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