背景:结直肠癌(CRC)是全球男性和女性中第三大广泛的癌症,见证一个令人担忧的崛起,尤其是在年轻人口统计学中。非受体酪氨酸激酶c-Src的异常激活与几种人类癌症的发展有关,包括结直肠,乳房,肺,和胰腺的。c-Src和己糖激酶2(HK2)之间的相互作用引发酶磷酸化,显著促进糖酵解,并最终促进儿童权利委员会的发展。
目的:本研究的目的是研究新鉴定的突变对c-Src与HK2酶之间相互作用的影响,并发现能够破坏这种相互作用的有效植物化合物。
方法:在本研究中,我们利用分子对接检查鉴定的突变对c-Src与HK2结合的影响.虚拟药物筛选,MD模拟,和结合自由能用于鉴定针对c-Src和HK2结合界面的有效药物。
结果:在这些突变中,六(W151C,L272P,A296S,A330D,R391H,和P434A)被观察到显着破坏c-Src结构的稳定性。此外,通过分子对接分析,我们证明了c-Src的突变形式表现出与HK2的高结合亲和力。野生型的对接评分为-271.80kcal/mol,而突变体显示的分数为-280.77kcal/mol,-369.01千卡/摩尔,-324.41千卡/摩尔,-362.18kcal/mol,266.77千卡/摩尔,W151C为-243.28kcal/mol,L272P,A296S,A330D,R391H,和P434A分别。此外,我们确定了五种铅植物化合物,显示出强烈的阻止c-Src与HK2酶结合的潜力,对于结肠癌的进展至关重要。这些化合物表现出与c-Src的牢固结合,对接评分为-7.37kcal/mol,-7.26千卡/摩尔,-6.88千卡/摩尔,-6.81千卡/摩尔,和-6.73千卡/摩尔。此外,这些化合物表现出动态稳定性,结构密实度,和最低的残余波动在MD模拟。前五次命中的结合自由能(-42.44±0.28kcal/mol,-28.31±0.25kcal/mol,-34.95±0.44kcal/mol,-38.92±0.25kcal/mol,和-30.34±0.27kcal/mol),进一步确认这些药物与c-Src的强相互作用,这可能阻碍驱动结肠癌进展的级联事件.
结论:我们的发现是一个有希望的基础,为未来在对抗结直肠癌方面的发现铺平了道路。
BACKGROUND: Colorectal cancer (CRC) stands as the third most widespread cancer worldwide in both men and women, witnessing a concerning rise, especially in younger demographics. Abnormal activation of the Non-Receptor Tyrosine Kinase c-Src has been linked to the advancement of several human cancers, including colorectal, breast, lung, and pancreatic ones. The interaction between c-Src and Hexokinase 2 (HK2) triggers enzyme phosphorylation, significantly boosting glycolysis, and ultimately contributing to the development of CRC.
OBJECTIVE: The objectives of this study are to examine the influence of newly identified mutations on the interaction between c-Src and the HK2 enzyme and to discover potent phytocompounds capable of disrupting this interaction.
METHODS: In this study, we utilized molecular docking to check the effect of the identified mutation on the binding of c-Src with HK2. Virtual drug screening, MD simulation, and binding free energy were employed to identify potent drugs against the binding interface of c-Src and HK2.
RESULTS: Among these mutations, six (W151C, L272P, A296S, A330D, R391H, and P434A) were observed to significantly disrupt the stability of the c-Src structure. Additionally, through molecular docking analysis, we demonstrated that the mutant forms of c-Src exhibited high binding affinities with HK2. The wildtype showed a docking score of -271.80 kcal/mol, while the mutants displayed scores of -280.77 kcal/mol, -369.01 kcal/mol, -324.41 kcal/mol, -362.18 kcal/mol, 266.77 kcal/mol, and -243.28 kcal/mol for W151C, L272P, A296S, A330D, R391H, and P434A respectively. Furthermore, we identified five lead phytocompounds showing strong potential to impede the binding of c-Src with HK2 enzyme, essential for colon cancer progression. These compounds exhibit robust bonding with c-Src with docking scores of -7.37 kcal/mol, -7.26 kcal/mol, -6.88 kcal/mol, -6.81 kcal/mol, and -6.73 kcal/mol. Moreover, these compounds demonstrate dynamic stability, structural compactness, and the lowest residual fluctuation during MD simulation. The binding free energies for the top five hits (-42.44±0.28 kcal/mol, -28.31±0.25 kcal/mol, -34.95±0.44 kcal/mol, -38.92±0.25 kcal/mol, and -30.34±0.27 kcal/mol), further affirm the strong interaction of these drugs with c-Src which might impede the cascade of events that drive the progression of colon cancer.
CONCLUSIONS: Our findings serve as a promising foundation, paving the way for future discoveries in the fight against colorectal cancer.