OBJECTIVE: This work aims to explore the PubChem library for novel VEGFR-2 kinase inhibitors. 1H-Indazole-containing drug AXITINIB, or AG-013736 (FDA approved), is chosen as a rational molecule for drug design. This scaffold proved its efficiency in treating cancer and other diseases as well.
METHODS: The present study used the virtual screening of the database, protein preparation, grid creation, and molecular docking analyses.
RESULTS: The protein was validated on different parameters like the Ramachandran plot, the ERRAT score, and the ProSA score. The Ramachandran plot revealed that 92.1% of the amino acid residues were located in the most favorable region; this was complemented by an ERRAT score (overall quality factor) of 96.24 percent and a ProSA (Z score) of -9.24 percent. The Lipinski rule of five was used as an additional filter for screening molecules. The docking results showed values of binding affinity between -14.08 and -12.34 kcal/mol. The molecule C1 showed the highest docking value of -14.08 Kcal/mol with the maximum number of strong H-bonds by -NH of pyridine to amino acid Cys104 (4.22Å), -NH of indazole to Glu108 (4.72), and Glu70 to bridge H of -NH. These interactions are similar to Axitinib docking interactions like Glu70, Cys104, and Glu102. The docking studies revealed that pi-alkyl bonds are formed with unsubstituted pyridine, whereas important H-bonds are observed with different substitutions around -NH. Based on potential findings, we designed new molecules, and molecular docking studies were performed on the same protein along with ADMET studies. The designed molecules (M1-M4) also showed comparable docking results similar to Axitinib, along with a synthetic accessibility score of less than 4.5.
CONCLUSIONS: The docking method employed in this work opens up new possibilities for the design and synthesis of novel compounds that can act as VEGFR-2 tyrosine kinase inhibitors and treat cancer.
目的:本工作旨在探索新型VEGFR-2激酶抑制剂的PubChem文库。含1H-咪唑的药物AXITINIB,或AG-013736(FDA批准),被选为药物设计的合理分子。这种支架也证明了其在治疗癌症和其他疾病方面的有效性。
方法:本研究使用数据库的虚拟筛选,蛋白质制备,网格创建,和分子对接分析。
结果:在Ramachandran图等不同参数上验证了蛋白质,ERRAT得分,和ProSA评分。Ramachandran图显示92.1%的氨基酸残基位于最有利的区域;这得到了96.24%的ERRAT评分(整体质量因子)和-9.24%的ProSA(Z评分)的补充。Lipinski规则5用作筛选分子的附加过滤器。对接结果显示在-14.08和-12.34kcal/mol之间的结合亲和力值。分子C1显示出-14.08Kcal/mol的最高对接值,吡啶的-NH与氨基酸Cys104(4.22an)的强H键的最大数量,-吲哚的NH至Glu108(4.72),和Glu70桥接-NH的H。这些相互作用类似于Axitinib对接相互作用,如Glu70,Cys104和Glu102。对接研究表明,pi-烷基键与未取代的吡啶形成,而重要的H键在-NH周围有不同的取代。根据潜在的发现,我们设计了新的分子,分子对接研究与ADMET研究一起对相同的蛋白质进行。设计的分子(M1-M4)也显示出与阿西替尼相似的对接结果,综合可达性评分低于4.5。
结论:这项工作中采用的对接方法为设计和合成可用作VEGFR-2酪氨酸激酶抑制剂并治疗癌症的新型化合物开辟了新的可能性。