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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Bioinformatics and computational exploration of novel inhibitors targeting KRAS G12C mutant protein in lung
Guohua Tang1, Hao Ding1, Yuehong Gong2
1Department of pharmacy, The First Affiliated Hospital of Xinjiang Medical University, 830011, Urumqi, Xinjiang, China.
Background:
The KRAS p.G12C mutation is a major oncogenic driver in lung adenocarcinoma (LUAD), a prevalent subtype of non-small cell lung cancer (NSCLC). The development of sotorasib has provided a new targeted therapeutic option for patients with this mutation.
Methods:
KRAS G12C mutations and expression in LUAD were analyzed. A pharmacophore model-based screening of over 1.4 billion conformations was conducted. Molecular docking, drug-likeness, pharmacokinetics, and toxicity predictions were carried out to explore ligands. Binding stability and key residue interactions were evaluated using extra-precision docking, molecular dynamics, H-bond lifetimes, FEL, PCA, and MM-GBSA analyses.
Results:
KRAS mutations were identified in 36% of LUAD samples, with G12C being the most frequent. KRAS p.G12C expression was significantly elevated in mutants (log₂FC = 0.68, p < 0.0001), with strong diagnostic accuracy (AUC = 0.90). A pharmacophore model based on the KRAS p.G12C-sotorasib complex identified 320 compounds. Top candidates, filtered by docking scores, drug-likeness, and toxicity, underwent extra-precision docking and 500 ns molecular dynamics simulations. RMSD, RMSF, Rg, SASA, buriedSASA, hydrogen bond dynamics, FEL and PCA revealed distinct dynamic behaviors among ligands. Key ligands, including PubChem-137,082,465, PubChem-137,304,698, PubChem-137,304,606, and PubChem-154,677,904, demonstrated favorable predicted binding interactions and dynamic stability, with in silico profiles broadly comparable to that of sotorasib. MM-GBSA and per-residue decomposition indicated ARG68, TYR96, and GLN99 as conserved interaction residues critical for ligand stabilization.
Conclusions:
The compounds, including PubChem-137,082,465 and PubChem-154,677,904, exhibited favorable binding and favorable interaction profiles, comparable to sotorasib, positioning them as computationally prioritized candidates for KRAS p.G12C inhibition in LUAD.
Insights
New drug candidates targeting the KRAS p.G12C mutation in lung adenocarcinoma show promise. Computational analysis revealed compounds with binding profiles similar to sotorasib, offering potential new treatments for non-small cell lung cancer.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- KRAS p.G12C mutation is a key driver in lung adenocarcinoma (LUAD), a common non-small cell lung cancer (NSCLC).
- Sotorasib is an existing targeted therapy for this mutation.
Purpose of the Study:
- To identify novel drug candidates targeting KRAS p.G12C.
- To computationally evaluate potential inhibitors for LUAD treatment.
Main Methods:
- Pharmacophore modeling and virtual screening of over 1.4 billion conformations.
- Molecular docking, drug-likeness, pharmacokinetic, and toxicity predictions.
- Molecular dynamics simulations and binding stability analyses (H-bond lifetimes, FEL, PCA, MM-GBSA).
Main Results:
- KRAS mutations found in 36% of LUAD, with G12C being most frequent.
- 320 potential compounds identified via pharmacophore screening.
- Several candidates, including PubChem-137,082,465 and PubChem-154,677,904, showed favorable binding and dynamic stability comparable to sotorasib.
- ARG68, TYR96, and GLN99 identified as critical interaction residues.
Conclusions:
- Identified novel compounds with favorable binding and interaction profiles for KRAS p.G12C inhibition.
- These candidates are computationally prioritized for LUAD treatment, showing potential comparable to sotorasib.
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