Furopyridine Derivatives as Potent Inhibitors of the Wild Type, L858R/T790M, and L858R/T790M/C797S EGFR.

IF 2.8 2区 化学 Q3 CHEMISTRY, PHYSICAL
The Journal of Physical Chemistry B Pub Date : 2024-12-19 Epub Date: 2024-12-05 DOI:10.1021/acs.jpcb.4c06246
Duangjai Todsaporn, Alexander Zubenko, Victor G Kartsev, Panupong Mahalapbutr, Athina Geronikaki, Samvel N Sirakanyan, Lyudmila N Divaeva, Victoria Chekrisheva, Ilkay Yildiz, Kiattawee Choowongkomon, Thanyada Rungrotmongkol
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引用次数: 0

Abstract

The treatment of patients with nonsmall cell lung cancer (NSCLC) using epidermal growth factor receptor (EGFR) inhibitors is complicated by drug-sensitive activating L858R/T790M and L858R/T790M/C797S mutations. To overcome drug resistance, a series of furopyridine (PD) compounds were virtually screened to identify potent EGFR inhibitors using molecular docking and molecular dynamics (MD) simulations based on the solvated interaction energy (SIE) method. Several PD compounds identified from virtual screening demonstrated the potential to suppress both wild-type and mutant forms of EGFR, with IC50 values in the nanomolar range. Among these, PD18 and PD56 exhibited highly potent inhibitory activity against both wild-type and mutant forms of EGFR, surpassing the efficacy of known drugs. Additionally, both PD compounds were cytotoxic to NSCLC cell lines (A549 and H1975) while being nontoxic to normal cell lines (Vero). The interaction mechanisms of both PD compounds complexed with wild-type and mutant forms of EGFR were elucidated through 500 ns molecular dynamics simulations. The predicted binding affinity from molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) correlated well with the experimental binding affinity derived from IC50 values. Furthermore, it was observed that van der Waals interactions, rather than electrostatic interactions, played a significant role in interacting with EGFR's active site. The strong inhibitory activity against EGFR was attributed to two key residues, M793 and S797, via hydrogen bonding, corresponding with lower solvent accessibility and a higher number of atomic contacts. Therefore, these potent compounds could be developed as promising drugs targeting both wild-type and mutant EGFR for the treatment of NSCLC.

呋喃吡啶衍生物作为野生型、L858R/T790M和L858R/T790M/C797S EGFR的有效抑制剂
使用表皮生长因子受体(EGFR)抑制剂治疗非小细胞肺癌(NSCLC)患者存在药物敏感激活L858R/T790M和L858R/T790M/C797S突变。为了克服耐药性,利用基于溶剂化相互作用能(SIE)方法的分子对接和分子动力学(MD)模拟,对一系列糠吡啶(PD)化合物进行了虚拟筛选,以确定有效的EGFR抑制剂。通过虚拟筛选鉴定出的几种PD化合物显示出抑制野生型和突变型EGFR的潜力,IC50值在纳摩尔范围内。其中,PD18和PD56对野生型和突变型EGFR均表现出极强的抑制活性,超过了已知药物的效果。此外,两种PD化合物对非小细胞肺癌细胞系(A549和H1975)具有细胞毒性,而对正常细胞系(Vero)无毒。通过500 ns分子动力学模拟,阐明了两种PD化合物与野生型和突变型EGFR复合物的相互作用机制。由分子力学/泊松-玻尔兹曼表面积(MM/PBSA)预测的结合亲和力与由IC50值得出的实验结合亲和力具有良好的相关性。此外,我们观察到范德华相互作用,而不是静电相互作用,在与EGFR活性位点相互作用中发挥重要作用。对EGFR的强抑制活性归因于两个关键残基M793和S797通过氢键形成,对应于较低的溶剂接近性和较高的原子接触数。因此,这些有效的化合物可以作为靶向野生型和突变型EGFR治疗非小细胞肺癌的有前途的药物。
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来源期刊
CiteScore
5.80
自引率
9.10%
发文量
965
审稿时长
1.6 months
期刊介绍: An essential criterion for acceptance of research articles in the journal is that they provide new physical insight. Please refer to the New Physical Insights virtual issue on what constitutes new physical insight. Manuscripts that are essentially reporting data or applications of data are, in general, not suitable for publication in JPC B.
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