Employing QSAR to design synthetic accessible TRPM8 Inhibitors

Abstract

Abstract In this work, 53 α-phenylglycine amides were analyzed by a diverse range of in silico approaches like activity cliff, molecular docking, molecular dynamics and 3D-QSAR model construction. The analysis assisted the design new compounds that could potentially inhibit the Transient Receptor Potential Melastatin 8 (TRPM8). This non-selective cation channel has a link with some diseases such as migraine, overactive bladder, and prostate cancer. A hybrid QSAR model, with acceptable figures of merit (R2adj = 0.87, Q2LOO = 0.86, Q2ext = 0.75), was used to predict the pIC50 for various designed structures. The synthetic routes employed in previous works was used to guide structure planning ensuring synthetic accessibility. Druglikeness properties were analyzed by the SwissADME website to filter out non-suitable compounds. It was possible to create four prototypes with higher pIC50. All designed compounds can be readily synthesized and tested for TRPM8 inhibition.