Target prediction for the inhibitors of VEGFR۲ as anti-colorectal cancer compounds using similarity-based search methods

Colorectal cancer is among the diseases that little is known about its etiology. Like other cancers, colorectalcancer is the end result of a multifactorial, multi genetic, and multistage process. VEGFR۲ has been indicatedas a key factor of angiogenesis in many cancers as well as colorectal cancer. Its inhibition is underinvestigation as anti-angiogenesis cancer therapy. To investigate the multi-targeting characteristic ofVEGFR۲ inhibitors, we utilized a rational approach combined with similarity-based search methods to theprediction of targets from a list of colorectal cancer-related drug targets. Data mining workflow wasdeveloped using KNIME. The data was extracted from the ChEMBL۲۵ database. The Morgan fingerprintswere calculated by RDKit and ChemAxon. Tanimoto similarity index was calculated and the clustering ofthe inhibitors was done using a procedure implemented by KNIME. Proper activity thresholds and Tanimotoindex were optimized based on the obtained results and the method was validated using the available evidencefor the probable inhibition of the predicted targets from literature. Compounds were considered similar if theTanimoto score was > ۰.۷. Using the developed method, CDK۲, HER۱, and TGF-β۲ were predicted for theinvestigated VEGFR۲ inhibitors. CDK۲ was predicted for AT-۹۲۸۳, as a multi-targeted VEGFR۲ inhibitorusing the developed method, there is published evidence for the inhibition of CDK۲ by AT-۹۲۸۳ whichapproves the prediction capability of the developed method. In addition, we studied the interaction of AT-۹۲۸۳ with VGEFR۲ and CDK۲ using molecular docking and the obtained binding energy values were -۹.۲۰Kcal/mol and -۹.۶۰ Kcal/mol, respectively. The results from the molecular docking study were in goodagreement with reported experiments. According to the results, the developed method could be used for thetarget prediction with high reliability.

کلیدواژه ها:

Colorectal cancer ، Multi-target ، KNIME platform ، Molecular docking ، VGEFR۲