Abstract

Cancer is a challenging health disease and is characterized by atypical and unrestrained cell growth. It is the second foremost reason of deaths all over the world. Large neutral Amino acid Transporter 1 (LAT1), Forkhead Box M1 (FOXM1), and G1‐to‐S phase transition 1 (GSPT1) are widely recognized as cancer‐associated proteins that play a significant role in the growth and proliferation of cancer. The identification of small organic molecules with the capacity to inhibit the activity of these proteins is a promising strategy for cancer therapy. However, to target these proteins competently a better understanding of molecular recognition of ligand is required. The results presented in this thesis unveils the molecular mysteries of LAT1, FOXM1, and GSPT1 inhibition via small molecules using structure‐based approaches. In the case of LAT1, docking simulations of known inhibitors against the homology model allowed to derive a binding hypothesis that could explain the inherent activity trend among inhibitors. Finally, a virtual screening operation, backed‐up with the experimental testing, was successful in identifying novel ligands of LAT1, thus validating the binding mode. Encouraged by the results from LAT1, a similar structure‐based protocol was employed in the case of FOXM1. Our docking experiments using FOXM1 inhibitors led us to identify a binding hypothesis, and presently we are finalizing the compounds for experimental evaluation. In the case of GSPT1, docking studies were focused on comprehending the differential ligand binding specificities of phthalimide‐based PROteolysis TArgeting Chimeras (PROTACs) in mediating the degradation of GSPT1 via the CRL4CRBN E3 ligase system. The binding modes were in agreement with the observed biochemical data of the PROTACs. In the case of GABAA receptors (side‐project), an exhaustive sampling of the docking poses and their assessment in the light of biological data allowed us to rationalize the preferred selectivity of pyrazoloquinolinones for the α1+/β1- over the α1+/β3- subtype of GABAA receptors. Collectively, through using structure‐based methods guided by experimental data, we gained valuable insights into the molecular mechanism of inhibition of cancer‐related targets, as well as GABAA receptors. However, many research questions remain open related to these targets, particularly concerning to LAT1. The most interesting one concerns the possibility to target LAT1 via nonamino acid chemistry.