背景:v-RAF鼠肉瘤病毒同源物B1(BRAF)是人类癌症中最常见的突变激酶之一。BRAF表现出三类突变:I类单体突变体(BRAFV600),II类BRAF同源二聚体突变体(非V600),和III类BRAF异源二聚体(非V600)。
方法:在本手稿中,所有三个突变体的蛋白质-配体相互作用位点:BRAF单体,已经讨论了BRAF同二聚体BRAF2:14-3-32和BRAF异二聚体BRAF:14-3-32:MEK(丝裂原细胞外激酶)。FDA批准的药物对所有三类突变体仍然有限制,特别是针对第二和第三类。使用DesPot网格模型,设计了1114个新化合物。使用虚拟筛选,用于单体的三个PDBIDS4XV2,7MFF为同源二聚体,和4MNE的异二聚体用于1114个新设计的化合物。
结果:Dabrafenib,恩科拉非尼,索拉非尼和维罗非尼作为标准药物。鉴定了每种蛋白质的前10个命中分子。使用对每个PDB标识符的蛋白质-配体位点的分子对接研究进行另外的结合研究。吸收,分布,新陈代谢,我们还进行了排泄(ADME)和毒性研究.
结论:确定在所有三类突变体中,最高命中分子具有比标准更好的结合和相互作用活性。
BACKGROUND: v-RAF murine sarcoma viral homolog B1 (BRAF) is one of the most frequently mutated kinases in human cancers. BRAF exhibits three classes of mutations: Class I monomeric mutants (BRAFV600), class II BRAF homodimer mutants (non-V600), and class III BRAF heterodimers (non-V600).
METHODS: In this manuscript, the protein-ligand interaction site of all three mutants: BRAF monomer, BRAF homodimer BRAF2:14-3-32, and BRAF
heterodimer BRAF:14-3-32:MEK (Mitogen extracellular Kinase) has been discussed. FDA-approved drugs still have limitations against all three classes of mutants, especially against the second and third classes. Using the DesPot grid model, 1114 new compounds were designed. Using virtual screening, the three PDB Ids 4XV2 for monomers, 7MFF for homodimers, and 4MNE for heterodimers were used for 1114 newly designed compounds.
RESULTS: Dabrafenib, encorafenib, sorafenib and vemurafenib were included as standard drugs. The top 10 hit molecules were identified for each protein. Additional binding studies were performed using molecular docking studies on the protein-ligand site of each PDB identifier. Absorption, distribution, metabolism, excretion (ADME) and toxicity studies were also performed.
CONCLUSIONS: It was identified that top-hit molecules had better binding and interaction activity than standard in all three classes of mutants.