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Grants

BioExcel-2

Funding Agency: European Commission, Horizon 2020 Framework Programme

Funding for NBD: 123.375,00

Reference Number: 823830

Link: https://bioexcel.eu/

Duration: January 2020 - June 2022

BioExcel is the leading European Centre of Excellence for Computational Biomolecular Research. Established in 2015, the centre has grown into a major research and innovation hub for scientific computing. BioExcel develops some of the most popular applications for modelling and simulations of biomolecular systems. A broad range of additional pre-/post-processing tools are integrated with the core applications within user-friendly workflows and container solutions. The software stack comes with great performance and scalability capabilities for extreme-scale utilization of the worlds largest high-performance computing (HPC) and high-throughput computing (HTC) compute resources. BioExcel has developed an extensive training program to address competence gaps in extreme-scale scientific computing for beginners, advanced users and HPC/HTC system maintainers. The centre maintains an extensive and growing network of industrial researchers in the pharmaceutical, chemical and food industries, and offers tailored products and consultancy services, while code development is done in close collaborations with hardware and software vendors to ensure compatibility and support for cutting-edge features. BioExcel works closely with various governmental, non-profit, educational and policy projects and initiatives.
NBD is involved in different areas of BioExcel-2. From the business perspective, NBD has been involved in the creation of BioExcel Enterprises giving its experience in the pharma and biotech market. As NBD is used to work with different clients, it knows its needs and market opportunities. From the scientific perspective, NBD is collaborating in the design and development of several workflows with BioExcel Tools to be implemented for academia and industry. NBD brings scientific knowledge and market experience to the project.


euCanSHare

Funding Agency: European Commission, Horizon 2020 Framework Programme

Funding for NBD: 201.250,00

Reference Number: 825903

Link: http://www.eucanshare.eu/

Duration: December 2019 - December 2023

euCanSHare is a joint EU-Canada project to establish a cross-border data sharing and multi-cohort cardiovascular research platform. Specifically, the project will integrate data infrastructures, IT solutions and data sources from EU, Canada and other countries into a web-based data access system with functionalities for increased efficiency in cardiovascular data-driven research. euCanSHare integrates more than 35 Canadian and European cohorts making up over 1 million records and actively seeks to expand to other regions.
The main activities advanced by NBD are to explore possible relationships between genotype (genetic change), protein mutations and their corresponding cardiovascular disease phenotypes. Using the European and Canadian cohorts data we are finding proteins statistically linked to the onset of CVD and matching them to their structures in the PDB (Protein Data Bank). The identified structures are being studied at the moment as well as a range of personalized variants following hints derived from the genomics studies in the euCanSHare virtual platform. A series of simulations (using HPC resources) are ongoing to explore the flexibility and molecular recognition of the proteins in different settings (wild type, pathological, genomic variants related to population sub- groups, etc). The results from the simulated structures will then be used for in silico virtual screening campaigns in search of new chemical entities.
Our study is particularly focused on the MAPKinases signalosome, but the principles used could be used by others to find other interesting targets through the euCanSHare platform.


OLIGOFASTX

Funding Agency: Centro para el Desarrollo Tecnológico Industrial (CDTi)

Funding for NBD: 716.282,40

Reference Number: MIG-20211028

Partners: SYLENTIS SA, APTATARGETS SL, APTUS BIOTECH SL, ARTHEX BIOTECH SL, BIOTECHNOLOGY DEVELOPMENT FOR INDUSTRY IN PHARMACEUTICALS SL, NANOVEX BIOTECHNOLOGIES SL

Duration: October 2020 - December 2024

OLIGOFASTX: Comprehensive platform for the sustainable development of oligonucleotide-based therapies
The OLIGOFASTX project pursues, as a general objective, to create a comprehensive platform for the development of new targeted therapies based on oligonucleotides for the treatment of rare diseases without medical response. Two of the greatest challenges facing these therapies lie in the low stability of these molecules in the blood, compared to other pharmaceutical compounds, and the development of new strategies for the synthesis of oligonucleotides that are more respectful of the environment. From NBD, a reference company in the development of in silico methods for the characterization of therapeutic compounds, the modeling of the impact of chemical modifications on the stability and activity of therapeutic oligonucleotides is proposed, thus reducing the number of molecules to be synthesized with the consequent cost reduction. On the other hand, NBD will fine-tune innovative strategies for the synthesis of naked and modified oligonucleotides using molecular modeling techniques for biocatalytic reactions, improving the processes for the synthesis and purification of oligonucleotides currently available.


VRSVAC

Funding Agency: Centro para el Desarrollo Tecnológico Industrial (CDTi)

Funding for NBD: 468.169,60

Reference Number: MIG-20211034

Partners: HIPRA SCIENTIFIC SLU, BIOTECHVANA SL, POLYPEPTIDE THERAPEUTIC SOLUTIONS SL

Duration: September 2020 - December 2024

Research of a new vaccine for human respiratory disease (VSRVAC)
The general objective of the project is to investigate a new vaccine based on mRNA transported in nanoparticles against RSV, which is capable of inducing dominant, effective and long-term memory cell responses against the virus.
NBD, a reference company in the in-silico design of biomolecules, will participate in the molecular research, engineering and optimization of the immunogenic potential of the encoded protein. This will require the investigation and implementation of bioinformatic tools and/or computational models aimed at describing the processes that activate and modulate the immune response against the vaccine. NBD will adapt the methodologies developed into software modules capable of being integrated into the NBD computing platform, thus transforming into new business solutions.


SARA

Funding Agency: Instituto de Salud Carlos III

Funding for NBD: 47.000,00

Reference Number: COV20/00505

Partners: CSIC, BSC

Duration: April 2020 - September 2021

This project proposes to address the inhibition of several types of coronavirus with a single molecule, which allows combating possible mutations of the SARS-CoV-2 virus that is responsible for the current pandemic, or other possible new coronaviruses that may emerge in the future.
This approach is based on the realization that any new antiviral drug must be ready when the virus appears and that if we are very specific in the antiviral drug for current SARS-CoV-2, it may be that said treatment is ineffective for future ones. Therefore, in the SARA project, it is proposed to accelerate the investigation of a polypharmacological approach that allows an antiviral therapy that realistically contemplates the uncertainty about the coronavirus that causes infections in the future and that increases the probability of having a useful drug considering the high mutability or the appearance of a new coronavirus.
Therefore, the SARA project proposes original research that addresses aspects not contemplated in the enormous and necessary efforts currently underway to urgently find efficient antiviral drugs for SARS-CoV-2. In the approaches focused on the search for specific drugs for SARS-CoV-2, there is a possible important problem that the SARA project is trying to solve and that has been revealed in the COVID19 pandemic. The realization that an antiviral therapy must be ready when the virus appears and that the development of a specific antiviral drug for the current SARS-CoV-2 may be ineffective for future infections.
NBD in collaboration with the BSC, conducted the main tasks related to molecular modelling at the hit-finding and hit-to-lead optimization stage. Multiple virtual screenings using a library (8 million compounds) of commercially available “drug-like” compounds extracted from the ZINC database as well as NBD proprietary ChemistriX database against multiple Mpro proteins from SAR-Cov-1, SAR-Cov-2 and MERS were executed. A collection of the fragments extracting from subsets of good binders were then subjected to FragHop and FragPELE to optimize the covalent-scaffold. At the hit-to-lead step, multiple tools in structural based drug design, using covalent/noncovalent dockings and FragPELE simulations were applied to evaluate the ligand binding modes and ligand-protein interactions to predict and optimize the chemical modification for more potent covalent inhibitors.


Fellowships

FragPELE

Funding Agency: Ministry of Science

Beneficiary: Chiara Pallara

Funding for NBD: 83.160,00

Reference Number: PTQ2019-010664

Partners: N/A

Development of a computational methodology to dynamically grow fragments in the presence of their target macromolecule
Drug discovery units are adopting fragment-based design (FBDD) as alternative technologies to high throughput screening (HTS). Experimental techniques are very expensive, so to develop new reliable theoretical methods will be essential to grow the different chemical groups R that decorate the initial fragment. In particular, being able to carry out massive in silico screening of R groups, in an automatic way, on a fragment whose binding mode is known would allow to advance FBDD techniques significantly.
This project is related to a new functionality of the NBD simulation platform, named FragPELE. It is intended that a fragment bound within its receptor grows through one or more vectors (R-groups) dynamically, that is, using the large sampling capacity of the original PELE code. Apart from typical small molecules this project will improve and optimize the current version by defining libraries of R groups for different problems such as growing peptides on their target proteins.
Currently, there are no affordable and computationally efficient technologies to sift through R group libraries dynamically. FragPELE will be an important and synergistic addition to several functionalities that NBD is already developing.


BioethanolPluriZyme

Funding Agency: Ministry of Science

Beneficiary: Joan Coines

Funding for NBD: 82.530,00

Reference Number: PTQ2020-011290

Partners: N/A

Development of PluriZymes for the sustainable degradation of lignocellulosic biomass
In the face of the current climate emergency, Europe is moving towards an economic model that will stand out for reducing the consumption of fossil resources. One of the key points to be developed is obtaining advanced biofuels through the use of enzymes. In fact, the enzymatic degradation of lignocellulosic biomass (or woody biomass) is a clearly more sustainable process than current methodologies, such as thermochemical processes. Since this biomass is the most abundant raw material to produce biofuels and is made up of lignin, cellulose and hemicellulose, glucosidases have been the main candidates for its degradation. Even so, the use of these enzymes is still far from being optimal at an industrial level. The recent discovery of the Lytic Polysaccharide Monooxygenases (LPMOs) class of enzymes has aroused enormous interest, since they are not only capable of degrading woody biomass through oxidative reactions, but also produce a synergistic effect on the hydrolytic activity of glycosidases.. However, there is still room for improvement of enzymatic processes. One of the most attractive strategies for this task is protein engineering, which is based on making point mutations in the protein’s amino acid sequence. Both experimental and computational techniques can be used to guide the process, the latter being the least expensive. Very recently, a new and powerful strategy has been developed, the PluriZymes design. These are enzymes in which a new active center has been computationally designed, in such a way that two (or more) active centers can coexist per enzyme unit or introduce others with complementary activities. This technique opens up a wide range of possibilities for the use of enzymes in industry.
In this present proposal, it is desired to design a PluriZyme LPMO. It is intended to develop a PluriZyme that contains the active center with the presence of copper typical of LPMO, and introduce the catalytic amino acids of glucosidases in another region of the enzyme. This would allow using the synergy between the two types of enzymatic catalysis, but using only one enzyme, greatly increasing the efficiency of the process.


Targeting RNA

Funding Agency: Ministry of Science

Beneficiary: Javier Iglesias

Funding for NBD: 110.040,00

Reference Number: PTQ2020-011291

Partners: N/A

Development of a computational methodology for the identification and optimization of RNA-directed ligands
The traditional paradigm for drug design has had countless successes and has populated our pharmacopoeia with many of its star products. However, there is a consensus on its exhaustion, since it is increasingly expensive, slow and complex to obtain new drugs that show a therapeutic profile linked to protein binding. Thus, the mainstream in the pharmaceutical industry is exploring disruptive approaches that escape the traditional paradigm of target protein inhibition/antagonism. This is the case of biological therapies based on the use of aptamers or antibodies and those that attack the RNA before it gives rise to the pathological protein. In this way, it is expected to be able to act on proteins that are not apt to be activated with sufficient affinity by small ligands (ie traditionally considered undruggable) and at the same time act surgically on certain cellular processes, saving the collateral effects derived from the inevitable promiscuity of small molecules by proteins with similar cavities.
The therapeutic profile of RNA can be exploited through various strategies, although all of them have in common their use of nucleic acids as drugs, having to face the limitations that these molecules present due to their poor ADMET properties, including problems of distribution and metabolic stability, off effects -target, and toxicity due to immunostimulation. Although many technologies are being developed that try to solve these limitations, such as encapsulation and conjugation in nanoparticles (lipid or polymer), there is still no general solution that allows the extensive use of nucleic acid-based therapies. On the other hand, the discovery by Merck and Roche that small molecules can recognize specific RNAs, overriding their biological function, opens the door to using small molecules to attack pathological RNA, obviating the ADMET problems of nucleic acids mentioned above.
Unfortunately, the current libraries of small compounds specific for RNAs are still small, with very little diversity, and the screening procedure presents numerous problems linked to the presence of false positives. Therefore, it is necessary to develop new methodologies that complement the existing ones. We propose here to develop a new strategy based on the adaptation of structure-based drug design techniques developed for proteins to obtain RNA ligands. Our goal is to develop an integrated simulation platform that allows us to cover the entire rational design process, from the virtual screening of ligands, to their subsequent refinement. What is proposed here is an absolutely disruptive project that can bring rational design to the field of RNA ligands. If completed successfully, it would place Nostrum Biodiscovery in a leading position worldwide in an emerging field for the generation of new drugs.


Past-grants

PELE-MSM

Funding Agency: Ministry of Science

Beneficiary: SuwipaSaenoon

Funding for NBD: 69.352,50

Reference Number: PTQ-17-09103

Partners: N/A

In silico estimation of absolute free energy changes associated with the binding of a drug to its receptor


SwitchItOn

Funding Agency: Centro para el Desarrollo Tecnológico Industrial (CDTi)

Funding for NBD: 160.064,35

Reference Number: EXP 00103741 / CIIP-20172018

Partners: Polygene AG, University Zürich, TargetExKft

New genomic switches have been developed for allowing to turn on/off multiple (trans)genes independently of each other in vivo.
Cellular and animal models of human disease are fundamental for the exploration and characterization of disease pathophysiology, target identification, and in the in vivo evaluation of novel therapeutic agents and treatments. Animal models, mimicking multi factor based disease such as cancer, are of value to increase the chances that clinical trials will be successful and drugs will enter the market at lower costs, in a shorter time.
NBD has participated in the consortium to collaborate in the theoretical and rational design of the switch systems, through the application of computational predictions to guide the design and provide reduced lists of mutational variants that will be the candidates to be synthesized experimentally.
For the design and theoretical optimization of switch systems, there are currently no tools on the market and they will be developed in this project.
Therefore, NBD has focused on the following specific objectives:

  • Three-dimensional modeling of different switch systems;
  • Development of a computational protein optimization technology within a switch system context. The technology to be developed has the temporary name of SMA (System Mutational Analysis);
  • Automationof SMA technology;
  • Validationof SMA technology;
  • Design and theoretical evaluation of new switch systems.

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