From structural dynamics to drug repurposing: computational approaches in the context of precision medicine

Precision medicine represents a paradigm shift in therapeutic strategy, moving away from "one-size-fits-all" treatments toward approaches tailored to the unique characteristics of the patient. The success of this transition depends on the avail- ability of drugs acting on a wide variety of targets with high specificity. Within this context, G-protein coupled receptors (GPCRs) have emerged as key yet under- explored targets, with Somatostatin Receptors (SSTRs) and the Gastrin-Releasing Peptide Receptor (GRPR) standing as highly promising candidates due to their overexpression in various cancers and diseases. Furthermore, the enzyme Cluster of Differentiation 38 (CD38), which is implicated in aggressive malignancies like myeloid leukemia, currently lacks small-molecule inhibitors, severely limiting the possibility of effective targeted therapies. In this thesis, a combination of molecular docking and molecular dynamics sim- ulations were employed to investigate these three targets in depth. While SSTRs exist in five isoforms, selective drugs for all of them remain elusive. By comparing the behavior of all five isoforms in complex with the endogenous ligand, somato- statin, this study identifies structural features determinant for achieving higher selectivity. Specifically, we sampled a rare conformation of somatostatin bound to SSTR5 as compared to the other isofrorms, significantly modifying its interaction pattern within the lower portion of the binding pocket. An analogous study was conducted for GRPR, which currently has no approved small-molecule therapeu- tics. We investigated the receptor’s interaction with PD176252, the only known 7 ABSTRACT high-affinity small-molecule scaffold as to date, and a lower-affinity derivative to identify the dynamical features that stabilize ligands within the binding site. Furthermore, using Well-Tempered Metadynamics, we explored the binding and unbinding pathways of PD176252, revealing a path asymmetry where extracellu- lar loops 1 and 2 play a critical role in the ligand’s entry and exit. To address the therapeutic gap for CD38, a virtual screening protocol involving molecular dock- ing, molecular dynamics, and free-energy calculations was executed. A library of 6,947 molecules in advanced clinical trials was screened against the enzyme’s active site. Radotinib, a second-generation tyrosine kinase inhibitor, was iden- tified as a potential CD38 inhibitor, as it successfully reproduces the interaction patterns of the natural substrate, NAD+. Collectively, these studies provide a detailed atomistic understanding of ligand- target interactions and binding kinetics. By uncovering novel conformational states and identifying potential drug repurposing candidates, this work offers critical structural insights that facilitate the rational design of potent, selective therapies within the framework of precision medicine.