Identification of Lead Compounds As Antagonists of Protein Bcl-x_L with a Diversity-Oriented Multidisciplinary Approach

Abstract

We report on the use of a diversity oriented synthesis (DOS) approach that resulted in the generation of a set of libraries of compounds presenting novel structural cores. These chemical cores have been employed to design potential antagonists of the antiapoptotic protein Bcl-x(L) through reiterated steps of molecular docking calculations followed by experimental verification of binding. Our data suggest that the DOS approach is suitable to generate novel scaffolds, which can be employed to target protein-protein interactions.

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

“…Th ere are numerous examples of novel, biologically useful small molecules that have been discovered through the screening of DOS libraries 10 . Th is includes hits against ' challenging ' biological processes for which ' traditional ' libraries usually fail to provide suitable leads or even hits ( vide supra ) 66 . Th erefore, it is reasonable to argue that the development of diversity-driven synthetic approaches such as DOS represents signifi cant advancements in the fi eld of chemical biology, off ering a potentially powerful approach for the identifi cation of novel molecules with exciting biological properties.…”

A Marriage of Convenience: Combining the Power of Isocyanide‐Based Multicomponent Reactions with the Versatility of (Hetero)norbornene Chemistry

“…Norbornenyl compounds can be conveniently employed in this way, as in the examples summarised in Figure 3, but many other pluripotent substrates and many other transformations are still possible and the challenge to the diversity-oriented synthetic chemist will be to discover and to apply them. It is possible to argue about the significance and utility of such an approach and at the moment no conclusive answer can be given, although some pros can already be seen in the particular cases illustrated in this review: 1) most of the structures illustrated in Figure 3 possess features already displayed by natural products and therefore have a good chance of interacting with biological targets, because this is what natural products are for, 2) biological activities have already been demonstrated for some compounds, [41] by application of a multidisciplinary approach combining synthetic chemistry, molecular docking and NMR screening, and 3) according to a recent study, [47] drug candidates often lack basic nitrogens, resulting in failures at later stages of the drug validation, from which point of view the presence of tertiary amines in all the compounds shown in Figure 3 is indeed an advantage not often achievable when classic I-MCRs are employed.…”

“…This strategy served in the discovery of a novel class of inhibitors for the BcL-xL protein, [41] and studies directed towards increasing the potencies of such compounds through the addition of additional appendages are underway.…”

Diversity Oriented Synthesis: How and Why?

“…We have recently applied this approach to an oxabicyclic amino acid derivative 1 [11], obtained in enantiomerically pure [17]. Further optimisation of the molecular structures is in progress in order to improve properties and activity of these hits.…”