Abstract：
BACKGROUND: VEGFR-2 tyrosine kinase inhibitors are receiving a lot of attention as prospective anticancer medications in the current drug discovery process.
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.
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.
摘要：
背景：VEGFR-2酪氨酸激酶抑制剂作为当前药物发现过程中的前瞻性抗癌药物正受到广泛关注。
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。
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。
