Abstract
BackgroundThe most well-known cause of cancer deaths identified in female is breast cancer. Several drugs approved by the food and drug administration (FDA) for the treatment of breast cancer may have adverse health effects. This research is aimed at developing a QSAR model and utilize it to predict the inhibitive activities of newly designed novel compounds, examine their ADMET and drug-likeness properties and carry out molecular docking studies between the designed compounds and the VEGFR-2 receptors in order to identify the essential amino acid residues involved in protein–ligand interactions and possible mechanism of action of the designed compounds.ResultsThe first model was selected as the best because of its fitness statistically with the following assessment parameters: R2train = 0.832, R2adj = 0.79, R2ext = 0.62, Q2 = 0.68, and LOF = 0.14509. Compound 11 was selected as a template to design new powerful compounds based on its low residual and high pIC50 values. Majority of the designed compounds has predicted pIC50 greater than that of the lead compound and the standard drug (Sunitinib) used as reference. Molecular docking studies results of the designed compounds revealed that they have higher docking scores than the template and the reference drug (Sunitinib) and are found to bind to the VEGFR-2 receptor in a similar manner to the reference drug. Pharmacokinetics and ADMET properties revealed that the designed compounds passed drug-likeness criteria because they did not violate more than 1 Lipinski’s rule of Five, They are uniformly distributed to the brain and are assumed to penetrate the central nervous system and finally they are all found to non-toxic and orally bioavailable.ConclusionThe developed model was therefore found to be efficient in predicting the pIC50 of Anti breast cancer compounds that are yet to be synthesized and it also help in reducing the cost and synthetic duration the compounds. The result of this research confirmed that the designed compounds may be developed as novel VEGFR-2 inhibitors.
Highlights
The most well-known cause of cancer deaths identified in female is breast cancer
It is regarded that vascular endothelial growth factor receptor-2 (VEGFR-2) found in Human umbilical vein endothelial cell (HUVEC) cells had a significant purpose in the angiogenesis route that take parts in the conversion, acceleration, and infringement of breast cancer cells (Hicklin and Ellis 2005)
The role of the 2-pyrimidinamine frame in medicinal chemistry is popular. Many of these compounds serves as anticancer agent. 4,6-diaryl-2- pyrimidinamine derivatives suggest good activity in the field of medicine. 2-Pyrimidinamine scaffold is the fundamental frame of pazopanib and JNJ-17029259 which are regarded as VEGFR-2-inhibitors (Liu et al 2018)
Summary
The most well-known cause of cancer deaths identified in female is breast cancer. Several drugs approved by the food and drug administration (FDA) for the treatment of breast cancer may have adverse health effects. As a result, focusing on proliferative pathways which consequences in cell death through apoptosis is regarded as an effective way for fighting this disease (Chandrappa et al 2009) The most well-known kind of cancers identified in female is breast cancer. Raloxifene which are selective estrogen receptor modulators (SERMs) that rival with estradiol for binding with ERα in breast tissue are mostly used for the remedy of E R+ breast cancer (Wang et al 2009). Due to their adverse health effects in other tissues, many SERMs may have acute side effects, such as endometrial cancer (Leeuwen et al 1994). Many of these compounds serves as anticancer agent. 4,6-diaryl-2- pyrimidinamine derivatives suggest good activity in the field of medicine. 2-Pyrimidinamine scaffold is the fundamental frame of pazopanib and JNJ-17029259 which are regarded as VEGFR-2-inhibitors (Liu et al 2018)
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