Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies

Abstract

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Concepts and Core Principles of Fragment-Based Drug Design

“…Surface plasmon resonance (SPR) technique is a very powerful tool for the determination of binding events [38]. SPR can be used to measure the binding affinity, specificity, and kinetic parameters of biomolecular interactions between a variety of proteins, DNA/RNA, and small/complex molecules [39,40]. The target protein is first immobilized on a gold or silver sensor surface.…”

Guided by evolution: from biology oriented synthesis to pseudo natural products

“…This has also been exploited to assemble libraries t for drug discovery. 42,43 Natural products were truncated to their core scaffold while keeping functionalities intact, which could be used for derivatisation and growing of the scaffold. 42 The obtained libraries were used in a rescaffolding approach for the discovery of novel inhibitors.…”

“…The same library was also employed in the discovery of Cyclophilin D (CypD) inhibitors through high throughput screening combined with X-ray crystallography. 43 Tetrahydroquinoline derivative 27 was identied to bind into the S2 pocket (Scheme 9B). Rescaffolding of a known inhibitor led to compound 28 with signicant increase in potency and affinity to the protein.…”

“…The pseudo NP principle can be extended to more than two fragments. For instance, pyridone-, dihydrofuran-and pyran fragments were combined to form pyrano-furo-pyridones (43,PFP). desired tricyclic cores as different regioisomers (43a-d, Scheme 16).…”

Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion

“…Moreover, despite the debate within the literature on the relevance of 3-D fragments, 17,18 recent examples have validated the utility of enriching screening libraries with these motifs. [19][20][21] Diversity-oriented synthesis (DOS) is a strategy by which libraries of structurally diverse compounds are constructed in a rapid and synthetically efficient manner through the employment of divergent synthetic manipulations. [22][23][24][25] Whilst traditionally efforts in this eld were focussed on larger molecules, in recent years the application of this methodology toward the synthesis of novel 3-D fragments has emerged.…”