Dataset Information

In silico design of EGFR^{L858R/T790M/C797S} inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations.

ABSTRACT: The development of L858R/T790M/C797S mutations in EGFR is one of the main reasons for the emergence of resistance after third-generation treatment of non-small cell lung cancer (NSCLC). Therefore, the development of 4th generation drugs needs urgent attention. To overcome resistance, in silico drug discovery and Design approaches were employed on a library of 29 novel 9-heterocyclyl substituted 9H-purines derivatives with EGFR^{L858R/T790M/C797S} inhibition for anticancer activity against NSCLC. The COMSIA/EHA model (Q² = 0.584, R² = 0.816, and Rpred2 = 0.73) showed a stable and reliable predictive ability of NSCLC activity, which was tested by several validation methods. Molecular docking studies reveal crucial interactions with EGFR^{L858R/T790M/C797S} inhibition for NSCLC activity. Based on theoretical methods, we designed 10 new compounds with good activity potential, which were tested using ADMET properties. Next, the molecular docking results were examined by molecular dynamics simulations to verify the stability of hydrogen bonding interactions with important residues such as MET790, MET793 and SER797, which are essential for the design of 4th generation EGFR Inhibitors to combat drug-resistant NSCLC.

SUBMITTER: Hadni H

PROVIDER: S-EPMC9674911 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

In silico design of EGFR<sup>L858R/T790M/C797S</sup> inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations.

Hadni Hanine H Elhallaouia Menana M

Heliyon 20221114 11

The development of L858R/T790M/C797S mutations in EGFR is one of the main reasons for the emergence of resistance after third-generation treatment of non-small cell lung cancer (NSCLC). Therefore, the development of 4th generation drugs needs urgent attention. To overcome resistance, in silico drug discovery and Design approaches were employed on a library of 29 novel 9-heterocyclyl substituted 9H-purines derivatives with EGFR<sup>L858R/T790M/C797S</sup> inhibition for anticancer activity agains ...[more]

PMID: 36411890

Similar Datasets

Project description:A series of derivatives (5-14) were synthesized through the diazotization of sulfadiazine with active methylene compounds. The chemical structures of these newly designed compounds were validated through spectral and elemental analysis techniques. The antiproliferative potential of derivatives 5-14 was assessed against three distinct cancer cell lines (A431, A549, and H1975) using the MTT assay. The results revealed that compounds 8, 12, and 14 exhibited the most potent antiproliferative activity, with IC50 values ranging from 2.31 to 7.56 μM. Notably, these values were significantly lower than those of known EGFR inhibitors, including erlotinib, gefitinib, and osimertinib, suggesting the potential of these derivatives as novel antiproliferative agents. Furthermore, compound 12 was identified as the most potent inhibitor of both EGFRWT and EGFRT790M protein kinases, with IC50 values of 14.5 and 35.4 nM, respectively. These results outperformed those of gefitinib and osimertinib, which exhibited IC50 values of 18.2 and 368.2 nM, and 57.8 and 8.5 nM, respectively. Molecular docking studies of compounds 8, 12, and 14 within the ATP-binding sites of both EGFRWT and EGFRT790M corroborated the in vitro results when compared to erlotinib, gefitinib, and osimertinib. The docking results indicated that compound 8 exhibited a favorable binding affinity for both EGFRWT and EGFRT790M, with binding scores of -6.40 kcal mol-1 and -7.53 kcal mol-1, respectively, which were comparable to those of gefitinib and osimertinib, with binding scores of -8.01 and -8.72 kcal mol-1, respectively. Furthermore, an assessment of the most promising EGFR inhibitors (8, 12, and 14) using the egg-boiled method for their in silico ADME properties revealed significant lipophilicity, blood-brain barrier (BBB) penetration, and gastrointestinal (GIT) absorption. Collectively, our designed analogs, particularly compounds 8, 12, and 14, exhibit promising dual antiproliferative and EGFRWT and EGFRT790M kinase inhibitory properties, positioning them as efficient candidates for further therapeutic development.

Dataset Information

In silico design of EGFR^{L858R/T790M/C797S} inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations.

Publications

In silico design of EGFR<sup>L858R/T790M/C797S</sup> inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

In silico design of EGFRL858R/T790M/C797S inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations.

Publications

In silico design of EGFR<sup>L858R/T790M/C797S</sup> inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

In silico design of EGFR^{L858R/T790M/C797S} inhibitors via 3D-QSAR, molecular docking, ADMET properties and molecular dynamics simulations.