284462-37-9Relevant articles and documents
LEADOPT: An automatic tool for structure-based lead optimization, and its application in structural optimizations of VEGFR2 and SYK inhibitors
Li, Guo-Bo,Ji, Sen,Yang, Ling-Ling,Zhang, Rong-Jie,Chen, Kai,Zhong, Lei,Ma, Shuang,Yang, Sheng-Yong
, p. 523 - 538 (2015)
Lead optimization is one of the key steps in drug discovery, and currently it is carried out mostly based on experiences of medicinal chemists, which often suffers from low efficiency. In silico methods are thought to be useful in improving the efficiency of lead optimization. Here we describe a new in silico automatic tool for structure-based lead optimization, termed LEADOPT. The structural modifications in LEADOPT mainly include two operations: fragment growing and fragment replacing, which are restricted to carry out in the active pocket of target protein with the core scaffold structure of ligand kept unchanged. The bioactivity of the newly generated molecules is estimated by ligand efficiency rather than a commonly used scoring function. Twelve important pharmacokinetic and toxic properties are evaluated using SCADMET, a program for the prediction of pharmacokinetic and toxic properties. LEADOPT was first evaluated using two retrospective cases, in which it showed a very good performance. LEADOPT was then applied to the structural optimizations of the VEGFR2 inhibitor, sorafenib, and the SYK inhibitor, R406. Though just several compounds were synthesized, we have obtained some compounds that are more potent than sorafenib and R406 in enzymatic and functional assays. All of these have validated, at least to some extent, the effectiveness of LEADOPT.
Sorafenib sulfydryl derivative and application thereof
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Paragraph 0019-0021, (2021/04/10)
The invention belongs to the field of medicine, and relates to a sorafenib sulfhydryl derivative and application thereof, in particular to a sorafenib sulfhydryl derivative and application thereof in preparation of an anti-tumor drug targeted delivery carrier. The structure of the sorafenib sulfhydryl derivative is shown as the following formula, a sulfhydryl functional group is introduced into pyridine-2-formamide of an anti-tumor small-molecule targeted drug sorafenib, and sorafenib can be coupled to free amino of polypeptide through proper linker molecules by utilizing the sulfhydryl functional group, so that a sorafenib polypeptide conjugate is constructed, the conjugate can give play to the targeting effect and tumor inhibition effect of sorafenib at the same time, and can be used as a targeting delivery carrier of antitumor drugs.
Design, synthesis, docking, molecular dynamics and bioevaluation studies on novel N-methylpicolinamide and thienopyrimidine derivatives with inhibiting NF-κB and TAK1 activities: Cheminformatics tools RDKit applied in drug design
Tan, Ninghua,Wang, Linxiao,Wang, Zhe,Zhang, Qian,Zhu, Wufu
, (2021/07/09)
Using cheminformatics tools RDKit and literature investigation, four series of 24 thienopyrimidine/N-methylpicolinamide derivatives substituted with pyrimidine were designed, synthesized and evaluated for activities against three cancer cell lines (MDA-MB-231, HCT116 and A549), TAK1 kinase and NF-κB signaling pathway. Almost all compounds showed selectivity toward the A549 cell lines and the most promising compound 38 could inhibit TAK1 kinase and NF-κB signaling pathway with the IC50 values of 0.58 and 0.84 μM. Moreover, 38 can induce cell cycle arrest of A549 cells at the G2/M checkpoint with 30.57% and induce apoptosis (34.94%) in a concentration-dependent manner. And western blot showed that compound 38 could inhibit TNF-α-induced IκBα phosphorylation, IκBα degradation, p65 phosphorylation and TAK1 phosphorylation, and reduce the expression of p65. What's more, the studies of docking, molecular dynamics, MM/PBSA and frequency analysis theoretically supported the conclusions of the bioevaluation.