Construction Of Irreversible Epidermal Growth Factor Receptor Inhibitors And 4D-QSAR Study Of Cannabinoid Receptor Inverse Agonists

For malignant tumors,surgical treatment only removes the local lesions,and cannot change the overall physical condition from the origin;most chemotherapeutic drugs have low selectivity,and they can also cause great toxicity to normal cells in the body,especially cells that proliferate rapidly.Therefore,it is of great significance to develop targeted drugs with high efficiency,high affinity and low side effects.EGFR plays an important role in the cell cycle and is related to cell growth,proliferation,and migration.EGFR is overexpressed in many kinds of tumor cells,such as non-small cell lung cancer,prostate cancer,pancreatic islet cancer,colon cancer,head and neck cancer,and glioma.Therefore,inhibiting the activity of EGFR can prevent its phosphorylation and signal transduction,play a multi-channel anti-tumor effect,and can also improve the therapeutic effect of radiotherapy and chemotherapy.The theoretical basis of this subject is computer-aided drug design.According to the structural characteristics of EGFR,with afatinib as the lead compound,20 acrylic ligand compounds were designed and synthesized.The reaction conditions are mild and the operation is simple.The synthesized target compounds are all confirmed by hydrogen nuclear magnetic resonance spectroscopy,infrared spectroscopy,carbon nuclear magnetic resonance spectroscopy,and mass spectrometry.After searching,there are no new compounds reported in the literature.Preliminary activity screening of the target compound found that compounds 1c,2e,1e,and 2d showed good activity,all reaching the micromolar level,respectively10.17 ng/ml,7.86 ng/ml,9.15 ng/ml,9.90 ng/ml,of which the IC₅₀ value of compound 2e Similar to the positive control drug gefitinib（8.14 ng/ml）.These four compounds with better activity were further molecularly docked,and it was found that the target compound mainly combined with the receptor amino acid residues through covalent bonds and hydrophobic effects to exert anti-tumor effects active.This result also proves the rationality of the design idea in reverse,and provides a new idea for the design and synthesis of ligand compounds with higher selectivity and better activity in the future.Since the emergence of two-dimensional quantitative structure-activity relationships（2D-QSAR）in the last century,quantitative structure-activity relationships have undergone three-dimensional and four-dimensional evolution process.The four-dimensional quantitative structure-activity relationship is simulated by molecular dynamics to generate conformational ensemble profiles（CEPs）for each compound,and then calculate a set of molecular 3D descriptors.This method makes up for the shortcomings that the results of the two-dimensional quantitative structure-activity relationship are not intuitive enough,and it is difficult to find the quantitative parameters of the new compound.At the same time,it breaks the limitations of the three-dimensional quantitative structure-activity relationship and combines the three-dimensional quantitative structure-activity relationship.Advantage.This study reported the 4D-QSAR and 3D-QSAR models of CB₂cannabinoid receptor inverse agonists for the first time.