FRAGMENTOME · FRAGMENT screening from advanced-sampling molecular dynamics simulations on a proteOME scale.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-05-01 → 2019-06-04
- EU contribution
- €158,122
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
FRAGMENT screening from advanced-sampling molecular dynamics simulations on a proteOME scale.
Fragment-Based Lead Discovery (FBLD) is a mainstream strategy for the generation of new drugs. In FBLD highly sensitive biochemical and biophysical screening technologies are used to detect the low-affinity binding of low-molecular-weight compounds (the so-called fragments) to biological targets that are involved in pathophysiological processes. Once a fragment hit is identified, the knowledge of the molecular interactions between the fragment and the target protein allows the rational generation of high-quality leads for drug development. Thus, high-resolution (e.g. X-ray crystallography) structure determination technologies are key to this approach but they can become a limiting factor for both technical and economical reasons. As a matter of fact, when the experimental characterisation of binding mode fails, the success rate of FBLD approaches drastically drops. To overcome current limitations in FLBD, here we have developed, and tested on more than hundreds of systems, a computational framework based on advanced-sampling molecular dynamics simulations to map the binding of fragments to protein surfaces on the high-throughput scale. The retrospective application of the developed tools to large datasets of fragment-protein complexes, including GPCR and kinases, find excellent agreement with experimental X-ray-based data and is now being used in a prospective manner within several collaborations established.
Data: CORDIS, © European Union
Project objective
In Fragment-Based Lead Discovery (FBLD) highly sensitive biochemical and biophysical screening technologies are used to detect the low-affinity binding of low-molecular-weight compounds (the so-called fragments) to biological targets that are involved in pathophysiological processes. Knowledge of the molecular interactions between fragment hit(s) and the target protein allows the rational generation of high-quality leads for drug development. Thus, high-resolution (e.g. X-ray crystallography) and relatively high-throughput structure determination technologies are key to this approach but they can become a limiting factor for both technical and economical reasons. As a matter of fact, when the experimental characterization of binding mode fails, the success rate of FBLD approaches drastically drops. To overcome current limitations in FLBD, here we propose the development of a computational framework based on advanced-sampling molecular dynamics simulations to map the binding of fragments to protein surfaces on the proteome scale---thus generating the Fragmentome Altas. For each individual target this will allow to: a) systematically identify fragments binding to protein surfaces and cryptic pockets; b) reconstruct the mechanism of binding with atomistic spatiotemporal resolution; c) characterize the molecular determinants of affinity and kinetics in fragment-protein complexes. This insight is fundamental for optimizing and evolving fragments to lead compounds with desired thermodynamics and kinetics features. To date, neither experimental nor computational approaches can provide such information at affordable costs while maintaining the high throughput needed for screening campaigns. The successful implementation of this ambitious project lies in the unique combination of expertise of its participants, and it will allow a novel state-of-the-art for modern drug discovery to be established. The Fragentome Atlas will be a freely accessible on-line server.
Original text from CORDIS.
Participants
- FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA) · BarcelonaCoordinatorSpain
Links
Data: CORDIS, © European Union