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Key driver in improving the performance of pharmaceutical industry
SPILLOproject provides a spectrum of specific services aimed at optimizing various phases of the drug discovery and development process.
We analyse the whole structural proteome of Homo sapiens and other organisms (e.g., Mus musculus, Rattus norvegicus) to highlight the potential target and off-target proteins of any small-molecule. Besides the experimentally solved protein structures available from the RCSB Protein Data Bank, which correspond to roughly 40% of the human proteome, as of July 2021 we also have the possibility to analyse the AlphaFold Protein Structure Database, whose protein structures are generated by artificial intelligence (AI) and cover nearly 100% of the human proteome.
RCSB Protein Data Bank
X-ray diffraction, solution NMR, cryo-EM (with redundancies)
AlphaFold Protein Structure Database
AI (without redundancies)
59,705 (Structural coverage of the h. proteome: ~ 40%)
23,390+ (Structural coverage of the h. proteome: ~100%
|Total:||71,658 (March 2023)||66,260+ (July 2021)|
Structural details concerning the location of the potential binding sites on the protein structures and the relative 3D-orientation of the molecule are also provided by the analysis.
Services related to THERAPEUTIC EFFECTS
A) Targets Unveiling for Known Therapeutic Effects. This service is valuable when the therapeutic effects of a small molecule, such as a drug on the market or still in development, are known, but the underlying biomolecular mechanisms remain unknown. The generated information offers several opportunities, including the ability to rationally modify the small molecule (Rational Drug Design) with the goal of enhancing its binding affinity towards the target(s) of interest. Furthermore, this knowledge facilitates the enhanced utilization of existing drugs on the market, leading to improved patient outcomes, particularly in the context of personalized medicine (Precision medicine).
B) Novel Targets for Drug Rescue/Repurposing. This service is extremely valuable for uncovering new applications of small molecules by identifying additional therapeutic targets that were previously unknown. The generated information enables the rescue of small molecules (Drug rescue) that were abandoned during development (e.g., due to lack of efficacy), despite their safety. It also facilitates the identification of potential new uses for drugs already on the market (Drug repurposing), especially as the patent expiration date approaches.
C) Drug Rescue/Repurposing by Similar Binding Sites. This service is highly valuable when you have a specific therapeutic target and a designated binding site (orthosteric or allosteric) in mind. By identifying similar binding sites on other targets, it becomes possible to discover existing molecules or drugs that can bind to the desired target and site, leading to drug rescue/repurposing opportunities.
Services related to ADVERSE DRUG REACTIONS (ADRs)
D) Identification of the off-targets responsible for known adverse drug reactions (ADRs) of a small molecule. This service is applicable in cases where a small molecule is known to induce one or more ADRs, but the underlying biomolecular mechanisms causing them remains unknown or not fully understood. The information generated serves as the foundation for designing rational modifications (Rational Drug Design) to the small molecule, with the goal of reducing its binding affinity towards undesired off-targets while maintaining the binding affinity towards the therapeutic target(s).
E) Identification of off-targets responsible for potential adverse drug reactions (ADRs) of a small molecule. This service is particularly beneficial for anticipating and predicting off-targets that may cause adverse effects, including rare ones, associated with a small molecule well in advance. The generated information proves highly useful in preventing the progression of unsafe molecules to later stages of drug development (Early toxicity prediction / De-risking strategy). Moreover, these insights can be leveraged to facilitate the design of rational drug modifications (Rational Drug Design), with the aim of minimizing binding affinity towards undesired off-targets while preserving the binding affinity towards the therapeutic targets.
F) Prioritising molecules based on their selectivity. This service aids in determining which molecules should be advanced to the next stages of drug development and which ones should be discarded, reducing the likelihood of late-stage candidate failures. Molecules are ranked according to the increasing number of their off-target interactions, which serves as an inverse measure of their selectivity. Molecules with numerous off-target interactions are less selective and more likely to induce adverse drug reactions (ADRs) compared to those with fewer off-target interactions (De-risking strategy). Furthermore, rational drug design aimed at eliminating interactions with unwanted off-targets is less complex for more selective molecules.
G) Multilevel cross-organism transferability analysis (MCOTA). Through the utilization of multilevel cross-organism transferability analysis (MCOTA) between H. sapiens and other organisms, such as R. norvegicus, M. musculus, C. elegans, D. rerio., D. melanogaster, etc., it becomes feasible to evaluate the predictive reliability of an animal model beforehand. This approach allows for an enhanced rational design of animal testing and improved interpretation of the results. If carried out in advance, MCOTA makes it possible to avoid unnecessary experiments and to design animal testing in a more targeted way, according to the 3Rs guiding principles.
The following checks and evaluations are performed:
1 - Verification of the presence of potential human target or off-target proteins identified by SPILLO-PBSS in the model organism (e.g., Rattus norvegicus).
2 - Calculation of the overall sequence identity between the human target or off-target protein and the corresponding protein in the model organism.
3 - Verification of the local similarity between the binding site within the human target or off-target protein and the corresponding protein of the model organism (i.e., by using SPILLO-PBSS to analyze a protein 3D-model of the model organism).
Vice versa, once identified the target proteins of the considered molecule in a model organism (e.g., Rattus norvegicus) by SPILLO-PBSS, the same analysis can be carried out to assess the transferability of the results to Homo sapiens. An example of MCOTA is described in this paper.
H) Customized services. As we make use of proprietary technologies developed in-house, we have the ability to tailor our services to the specific needs of our clients. This may include developing new features and exploring innovative ways of using our technologies. In this way, we are able to effectively meet their requirements and provide complete solutions that fully meet their needs.