CORDIS - EU research results

Diversity-Oriented Synthesis of Conformationally Constrained Peptidomimetics

Final Report Summary - DOS-PEPTIDOMIMETICS (Diversity-Oriented Synthesis of Conformationally Constrained Peptidomimetics)

We have developed a new and efficient reagent-based diversity-oriented synthesis (DOS) approach, starting from a-methyl-a-propargyl amino ester, to generate a high-quality screening library of 40 novel, structurally diverse and complex small molecules featuring a quaternary sterecocenter. The scope of our strategy in generating other sp3-substituted libraries was exemplified by the synthesis of an aryl-containing derivative. We have also validated the asymmetric synthesis of a given enantiomer of a molecule from our library starting from the optically pure quaternary (R)-amino ester following the same synthetic pathway used for the generation of the initial racemate.

The overall shape of a molecule and its electronic properties are the most fundamental factors controlling its biological effects. Consequently, in a DOS context, the greater the degree of structural diversity and complexity achieved within a certain library, the higher the probability of identifying new biologically active compounds. Thus, computational analyses (PMI plots) of our reported DOS library indicated a high level of molecular shape diversity. Further comparative plots of virtual libraries were useful to highlight that the presence of the quaternary stereocenter was essential to achieve this broad coverage within the molecular shape space. Thus, plots in which one (methyl) or both substituents were removed or substituted showed a marked change in the shape distribution. Moreover, as the MDS plot has showcased, the target library represents an attractive collection of biologically diverse small molecules with high scaffold and molecular shape diversity.

Currently, work is underway to investigate the in silico multi-target prediction aiming to identify potential hits against a broad variety of known biological targets. Accordingly, future work will be focused on the expansion of this synthetic strategy to additional ring sizes as well as the exploration of scaffold decorations.
(Manuscript prepared)

With our vision in research we contemplate that the efficient and simultaneous synthesis of large number of new structurally diverse small molecules, that can be assessed into different biological screenings (antibacterial, anticancer or phenotypic screenings), should deliver better clinical candidates, with better physicochemical profiles and with enhanced chances of becoming marketed drugs. There is no doubt that the success of this project will significantly impact in the way the global pharmaceutical industry discovers drugs going forward.

Accordingly to preliminary computational results in identifying potential hits against a broad variety of known biological targets, this project will provide untapped pharmacophore models for potential biological targets to be exploited by the Pharmaceutical Industry. Thus, we strongly believe that the implementation of this approach will directly contribute to improve the economic competitiveness of the EU, protecting the community’s international reputation, as well as the quality of life of its people.