Development of optimized pyrimido-thiazole scaffold derivatives as anticancer and multitargeting tyrosine kinase inhibitors using computational studies

Abstract

Cancer is one of the frontier causes of leading death ratesglobally and one of the most researched domains. Despite many drugs available in the market currently, their effectiveness towards resistance, randomly mutating cancer targets, and side effects initiate the necessity of developing target selective and effective anti-cancer drugs.This study aimed to develop a congeneric series of fused pyrimidine and thiazole-containing hybrid series and evaluate its anticancer potential using in-silico tools. Molecular modeling strategies were used to develop various derivatives of fused thiazole-pyrimidines as anticancer agents for target-based drug discovery. Strategically, based on Structural Activity Relationship (SAR), of the synthesized or studied compounds, a combinatorial library was generated using the lead grow tool to develop a possible combination of various derivatives. Using Swiss ADME and Osiris; the ADMETproperties were predicted and screened molecules were docked using Auto-dock vina and Swiss Dockto obtain possible interactions with 5 listed targets of Tyrosine Kinase Inhibitors (TKI's) namely BCR-ABL kinase (PDB- 2GQG), c-ABL Kinase (PDB-3PYY), EGFR(PDB-1M17), VEGFR(PDB- 4ASD), and BRAF inhibitors (PDB- 2FB8). SAR of the pyrimido-thiazole molecules was derived from the literature survey and substitutions that enhance the anticancer activity were incorporated into the Combilib to generate a library of 221 compounds. This library of compounds was subjected to a Lipinski Filter. About 45 compounds were screened and tested for their drug-likeliness parameters. The 24 compounds that qualified with good absorption, drug-likeliness, and ADME were tested for their toxicity for developing relatively safe drugs with low side effects. These molecules were docked intofivedifferent PDB's and their binding affinity scores along with prominent interactions were noted. Compound 33 has shown comparable binding affinity and key interactions with all the five PDB's and thus can be used as a lead for further investigations. These studies have helped to optimize the relationship between fused pyrimidine and thiazoles as anticancer Tyrosine Kinase Inhibitors.