Technological developments in Virtual Screening for the discovery of small molecules with novel mechanisms of action
[eng] Advances in structural and molecular biology have favoured the rational development of novel drugs thru structure-based drug design (SBDD). Particularly, computational tools have proven to be rapid and efficient tools for hit discovery and optimization. The main motivation of this thesis is to...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/197140 |
| Acceso en línea: | https://hdl.handle.net/2445/197140 http://hdl.handle.net/10803/688135 |
| Access Level: | acceso abierto |
| Palabra clave: | Biofísica Bioinformàtica Disseny de medicaments Biophysics Bioinformatics Drug design |
| Sumario: | [eng] Advances in structural and molecular biology have favoured the rational development of novel drugs thru structure-based drug design (SBDD). Particularly, computational tools have proven to be rapid and efficient tools for hit discovery and optimization. The main motivation of this thesis is to improve and develop new methods in the area of computer-based drug discovery in order to study challenging targets. Specifically, this thesis is focused on docking and Virtual Screening (VS) methodologies to be able to exploit non-standard sites, like protein-protein interfaces or allosteric sites, and discover bioactive molecules with novel mechanisms of action. First, I developed an automatic pipeline for binding mode prediction that applies knowledge- based restraints and validated the approach by participating in the CELPP Challenge, a blind pose prediction challenge. The aim of the first VS in this thesis is to find small molecules able to not only disrupt the RANK-RANKL interaction but also inhibit the constitutive activation of the receptor. With a combination of computational, biophysical, and cell-based assays we were able to identify the first small molecule binders for RANK that could be used as a treatment for Triple Negative Breast Cancer. When working with challenging targets, or with non-standard mechanisms of action, the relationship between binding and the biological response is unpredictable, because the biological response (if any) will depend on the biological function of the particular allosteric site, which is generally unknown. For this reason, we then tested the applicability of the combination of ultrahigh-throughput VS with low-throughput high content assay. This allowed us to characterize a novel allosteric pocket in PTEN and also describe the first allosteric modulators for this protein. Finally, as the accessible Chemical Space grows at a rapid pace, we developed an algorithm to efficiently explore ultra-large Chemical Collections using a Bottom-up approach. We prospectively validated the approach in BRD4 and identified novel BRD4 inhibitors with an affinity comparable to advanced drug candidates for this target. |
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