The present Thesis consists of different Medicinal Chemistry projects which include a combination of computational and experimental approaches to Drug Discovery. The final aim is to obtain small molecules of biological interest in anticancer and antibacterial chemotherapy. Projects #1 and #2 (Chapters 5 and 6) are focused on the rational design and synthesis of two new series of small molecules with a benzotriazole scaffold functionalized with an acrylonitrile moiety as new anticancer agents acting on tubulin assembly as CBSIs (colchicine–binding site inhibitors). The functionalization of the main scaffold with fluorine atoms in different positions (5',6' or 4', respectively) led to the synthesis of two new series of benzotriazole–based small molecules. The first approach focused on the application of Molecular Docking techniques to analyze the binding pose of the molecules at the interface between α– and β–tubulin, studying electrostatic and vdW interactions. The molecules showed a good binding profile, hence they were synthesized, characterized and biologically analyzed. They displayed a good antiproliferative activity and, through a specific biological assessment, they showed to interfere with tubulin assembly and to specifically compete with colchicine for its binding pocket on tubulin. Project #3 (Chapter 7) makes use of a fragment–based drug discovery (FBDD) approach aimed to find new fragments to build new inhibiting agents for a protein called WaaG. This target is a glycosyltransferase involved in the biosynthesis of the lipopolysaccharide (LPS), present in gram–negative bacteria, such as Escherichia coli. Two libraries of small molecules were screened through Molecular Docking simulations. The selected ones were more in–depth assessed through a Molecular Dynamics (MD) study, to calculate their Binding Free Energy (BFE) and related KD values, the root–mean–square deviation (RMSD) of the protein backbone (when bound to the ligands), but also protein–ligand electrostatic (mainly hydrogen bonds) and hydrophobic interactions. A study on the protein movement during the MD trajectory of WaaG apo–protein showed a dynamic behavior of both N– and C– domains one against each other, allowing to predict a twisting–like fashion of the protein. Project #4 (Chapter 8) is a synthetic study on 1,2–cis–glycosylation reactions, aimed to optimize yield and stereoselectivity of the reactions. The goal of the synthesis is a trisaccharide; NMR investigations are ongoing for the determination of the exact conformational state of the trisaccharide. Aeromonas salmonicida is a gram–negative bacterium whose outer membrane is made of lipopolysaccharide (LPS). In the O–antigen of its LPS there is a trisaccharide structurally similar to the synthesized trisaccharide building block. The full NMR characterization of the synthesized trisaccharide will be helpful in future Structure Elucidation investigations on A. salmonicida lipopolysaccharide

Computational and Synthetic Approaches to Drug Discovery in Anticancer and Antibacterial Chemotherapy / Riu, Federico. - (2022 Jan 31).

Computational and Synthetic Approaches to Drug Discovery in Anticancer and Antibacterial Chemotherapy

RIU, FEDERICO
2022

Abstract

The present Thesis consists of different Medicinal Chemistry projects which include a combination of computational and experimental approaches to Drug Discovery. The final aim is to obtain small molecules of biological interest in anticancer and antibacterial chemotherapy. Projects #1 and #2 (Chapters 5 and 6) are focused on the rational design and synthesis of two new series of small molecules with a benzotriazole scaffold functionalized with an acrylonitrile moiety as new anticancer agents acting on tubulin assembly as CBSIs (colchicine–binding site inhibitors). The functionalization of the main scaffold with fluorine atoms in different positions (5',6' or 4', respectively) led to the synthesis of two new series of benzotriazole–based small molecules. The first approach focused on the application of Molecular Docking techniques to analyze the binding pose of the molecules at the interface between α– and β–tubulin, studying electrostatic and vdW interactions. The molecules showed a good binding profile, hence they were synthesized, characterized and biologically analyzed. They displayed a good antiproliferative activity and, through a specific biological assessment, they showed to interfere with tubulin assembly and to specifically compete with colchicine for its binding pocket on tubulin. Project #3 (Chapter 7) makes use of a fragment–based drug discovery (FBDD) approach aimed to find new fragments to build new inhibiting agents for a protein called WaaG. This target is a glycosyltransferase involved in the biosynthesis of the lipopolysaccharide (LPS), present in gram–negative bacteria, such as Escherichia coli. Two libraries of small molecules were screened through Molecular Docking simulations. The selected ones were more in–depth assessed through a Molecular Dynamics (MD) study, to calculate their Binding Free Energy (BFE) and related KD values, the root–mean–square deviation (RMSD) of the protein backbone (when bound to the ligands), but also protein–ligand electrostatic (mainly hydrogen bonds) and hydrophobic interactions. A study on the protein movement during the MD trajectory of WaaG apo–protein showed a dynamic behavior of both N– and C– domains one against each other, allowing to predict a twisting–like fashion of the protein. Project #4 (Chapter 8) is a synthetic study on 1,2–cis–glycosylation reactions, aimed to optimize yield and stereoselectivity of the reactions. The goal of the synthesis is a trisaccharide; NMR investigations are ongoing for the determination of the exact conformational state of the trisaccharide. Aeromonas salmonicida is a gram–negative bacterium whose outer membrane is made of lipopolysaccharide (LPS). In the O–antigen of its LPS there is a trisaccharide structurally similar to the synthesized trisaccharide building block. The full NMR characterization of the synthesized trisaccharide will be helpful in future Structure Elucidation investigations on A. salmonicida lipopolysaccharide
medicinal chemistry; molecular docking; molecular dynamics; drug discovery; anticancer activity
anticancer activity
Computational and Synthetic Approaches to Drug Discovery in Anticancer and Antibacterial Chemotherapy / Riu, Federico. - (2022 Jan 31).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/255000
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