Development of novel small molecule inhibitors targeting angiotensin II type ۲ receptor against colorectal cancer

Background: Recent studies showed that the blockade of the angiotensin (ANG) II type ۲ receptor(AT۲R) can potentially inhibit tumor growth in several cancers, including colorectal cancer.Therefore, in this study, we designed potent and novel AT۲R inhibitors by using bioinformaticsoftware and online tools including Discovery Studio, Genetic Optimization for Ligand Docking(GOLD) Suite ۵.۲, and SwissADME toxicity prediction.Method: First, the protein structure of AT۲R in complex with EMA۴۰۱, one of the AT۲R inhibitors,was obtained from the Protein Data Bank server (PDB= ۷JNI). Then, the protein structurewas refined and prepared for docking by adding hydrogen using Discovery Studio software. Forthe next step, the potency of three FDA-approved drugs (Valsartan, Telmisartan, and Losartan)with the ability to inhibit AT۲R was predicted and compared with EMA۴۰۱ using GOLD software.Finally, a structure-based design and virtual screening (PubChem with TANIMOTO THRESHOLD۹۰%) were used to find new and potent lead compounds against AT۲R. The binding mode,total free energy changes, and interactions upon binding of newly designed inhibitors with AT۲Rwere predicated and visualized using GOLD and discovery studio software, respectively. Thedrug-like and chemical distribution, absorption, metabolism, excretion, and toxicity (ADMET)properties of newly designed inhibitors also were predicted using the SwissADME portal (http://www.swissadme.ch/).Result: The docking result showed that EMA۴۰۱ with higher Chemscore. Fitness (۶۰.۲۳) andlower Chemscore.DG (-۶۰.۶۶) binds to its receptor AT۲R compared with other ones includingValsartan, Telmisartan, and Losartan. Finally, among ۲۳ compounds that were selected basedon structure-based design and ۱۹۶۱ compounds selected based on virtual screening, TEL-۵ (aderivate of telmisartan), and two other ones with PubChem CID ۶۸۶۶۸۷۱ and ۱۵۶۳۲۸۷۹۳ weresuggested with higher affinity and favorable predicted ADME values than the EMA۴۰۱.Discussion: according to our results, these novel inhibitors including, TEL-۵ and two other onescan be suggested as potential compounds with AT۲R inhibitory activity to be used for the treatmentof colorectal cancer.