Tkachuk, OLEH (2025) Identification of new bioactive molecules by computational methods. [Tesi di dottorato]

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Abstract

This thesis explores the “language” of biomolecules, interpreting their interactions as a grammatical system in which protein domains, short linear motifs, and hot spots represent the fundamental units of communication with functional ligands. The structural and conformational properties of bioactive small molecules—derived either from rational design or from natural products used as “privileged scaffolds”—can mimic those of endogenous ligands, thereby speaking the same “language”. Building on this concept, various computational approaches were employed to investigate key protein interaction sites and their binding with both endogenous and exogenous functional ligands. The ultimate goal of these studies is to develop computational models as tools for identifying new lead compounds or optimizing existing ones. The chapters of this thesis describe: i) the role of stereochemistry in the activity of nature-inspired isooxazoline derivatives; ii) the design of tetrasubstituted pyrrole derivatives that mimic α-helix-based protein–protein interaction motifs; iii) the allosteric activation of the human 20S proteasome by charged porphyrins that mimic interactions with 20S regulatory proteins; iv) the interaction of 2-phenylimidazo[1,2-b]pyridazine derivatives with calcium channels, highlighting their antiepileptic and neuroprotective properties; v) a computer-aided SAR analysis of 1,2,4-thiadiazolidine-3,5-dione derivatives as selective covalent inhibitors of coronavirus cysteine proteases; vi) computational alanine-scanning mutagenesis of coronavirus non-structural proteins to identify novel druggable binding sites; vii) the investigation of PROTAC ternary complexes using Molecular Interaction Fields, focusing on linker optimization for selective degradation of BET family bromodomains. Collectively, these studies support the hypothesis that decoding the structural language of biomolecular actors is a powerful strategy in rational drug discovery and the design of innovative therapeutic agents.

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