Protein-protein interactions (PPIs) drugs can be divided into three categories according to their molecular weight, including small molecules, peptides and antibodies. PPI targets cannot be penetrated by large molecules, and small molecules are used as a viable option for drug development, as they have better transmembrane ability and cell permeability to reach cellular targets. However, the surface area of the PPI interface is large and highly hydrophobic, and there are few pockets on the surface for small molecule drugs to bind. On the other hand, drugs acting on PPI require a higher molecular weight (>500 Da) than traditional small molecule drugs, which is difficult to meet the Lipinski's Rule of Five. Therefore, small molecule drugs are difficult to become potent drugs. The discovery of protein hotspot regions offers the possibility of combination of PPI and small-molecule drugs. Among them, apoptosis pathway-related PPI targets are gradually manifesting clinical anticancer efficacy, mainly including MDM2-p53, Bcl family (Bcl-2, Bcl-xL/Bak, Bax) and IAP Caspases.
BOC Sciences has designed a series of PPI targeted libraries to generate structurally-diverse small-molecule screening compounds by employing a virtual molecular screening method.
Figure 1. In silico strategies for PPI drug discovery. (Joy, S.; et al. 2019)
Protein-Protein Interactions (PPI) Screening Library Design
A transmembrane protein called programmed cell death ligand 1 (PD-L1) binds to PD-1, thereby inhibiting cytokine secretion and suppressing the proliferation of PD-1-positive cells. BOC Sciences has introduced a receptor-based virtual screening method (molecular docking) to design a new PD-L1 targeted screening library to provide more than 2,000 structurally distinct screening compounds that disrupt PPI between the PD-1/PD-L1
At BOC Sciences, with the growing interest in PPI, a series of proprietary potential PPI modulators are produced through a ligand-based strategy for high-throughput screening projects in drug discovery. We have present the following three libraries: PPI Focused Library by Machine Learning, PPI Focused Library by 2D Similarity Search, PPI Focused Library by Rule of Four
The receptor-based approach to library design refers to the disruption of specific functional interactions between proteins, in which many of the most attractive PPI targets are collected. Our teams can use this method to generate potential PPI modulators including bromodomains, integrins, apoptosis regulators and oncoproteins belonging to different PPI types, and all of them have been proven to be druggable by small molecule compounds
To date, the PPI inhibitors discovered are significantly different compared to most of known drugs: they are typically larger, more hydrophobic, contain more aromatic rings. Most of the available chemical libraries are not suitable for screening PPI targets, PPI-focused libraries therefore need to be specifically designed to achieve the right chemical space. BOC Sciences is capable of designing a PPI helix-turn 3D-mimetic library, providing compounds with diverse and well-developed 3D shapes
Figure 2. Varied applications of molecular dynamics (MD) simulations in PPI research. (Joy, S.; et al. 2019)
PPIs have been shown to be important components in cellular signaling pathways as well as in important processes such as viral infection, replication and immunosuppression. To date, the main strategies for discovering small molecule modulators of PPI have been limited to structurally characterized targets. Recent developments in molecular scaffolds that mimic the side chain display of peptide secondary structures have yielded effective designs. BOC Sciences’ recognition element PPI library contains 26,000 compounds
Nature is three-dimensional and therefore recognizes small molecules in a complementary 3D-fashion, so if drugs are also three-dimensional, they may be more selective for their targets (especially in PPI). Our teams are committed to designing compounds with diverse and well-developed 3D shapes
Peptidomimetics are organic molecules that mimic the action of natural peptides or proteins, and they can effectively improve some of the properties of natural peptides, such as enhanced receptor affinity and selectivity, potency and good bioavailability. Therefore, the design and synthesis of peptide mimics undoubtedly has great potential for drug discovery. BOC Sciences has prepared a proprietary peptidomimetics screening library containing more than 5,800 α-helix and β-turn mimics that are selected using a ligand-based approach
- Peptidomimetics of Beta-Turn Motifs Library
The use of small-molecule mimetics of β-turn recognition motifs to mimic key interaction residues is an attractive approach to discovering modulators of protein-protein interactions. β-turn is one of the three major secondary structural motifs found in proteins and peptides, and occurs where the polypeptide strand reverses direction. In recent years, BOC Sciences has extensively investigated mimetics of β-turn with the aim of discovering compounds that can mimic or disrupt β-turn-mediated recognition events
Figure 3. Distributions of druggability scores and small-molecule 2D descriptors of PPI drugs/candidates and non-PPI ligands. (Ke, W.; et al. 2019)
Peptidomimetics are commonly used in the clinic to overcome problems that arise in the pharmacokinetic issues of therapeutic proteins and peptides. Peptidomimetics are able to mimic the structure of biologically active proteins or peptides while displaying acceptable pharmacokinetic properties, as well as maintaining the desired biological activity. The applicability of peptidomimetics has been demonstrated on different protein model systems including apoptosis regulators, transmembrane receptors, small GTPases and transcriptional regulators
The application of the Ugi reactions in the construction of new peptide scaffolds is an important goal of organic chemistry. Ugi four-component reaction (U-4CR) is widely considered to be very effective for the synthesis of pseudopeptides. BOC Sciences is committed to designing a high-quality circlic-ugi PPI library
The biological activity of any given molecule heavily depends on the 3D shape of its PPI library. Moreover, the molecular shape diversity of a small molecule library is the most important indicator of overall functional diversity. Considering this, BOC Sciences has designed a proprietary eccentric PPI library to provide a variety of structurally diverse molecular compounds
PDZ domains are abundant protein interaction modules that recognize short amino acid motifs at the C-termini of target proteins. They regulate a wide range of biological processes. Since PDZ domains have well-defined binding sites, they provide promising targets for further use of PPIs
Protein-Protein Interactions (PPI) Screening Library Characteristics
- High diversity over the screening set: mean Tanimoto > 0.85
- Favorable physicochemical parameters and solubility requirements
- No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
- Bioactivity and safety confirmed by preclinical studies and clinical trials
- Structural diversity, medicinal activity, and cellular penetration
- Structural document, IC50, and other chemical and biological data are provided
- All compounds are continually updated
- Compound cherry-picking service is provided
What We Deliver
- Delivered within 2 weeks in any customer-preferred format
- Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
- All compounds have a minimum purity of 90% assessed by 1H NMR and HPLC
- Analytical data is provided
BOC Sciences provides professional, rapid and high-quality services of Protein-Protein Interactions (PPI) Screening Library design at competitive prices for global customers. Personalized and customized services of Protein-Protein Interactions (PPI) Screening Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!
References
- Joy, S.; et al. Evolution of in silico strategies for protein-protein interaction drug discovery. Molecules. 2019. 23(8): 1963.
- Ke, W.; et al. Mimicking Strategy for Protein-Protein Interaction Inhibitor Discovery by Virtual Screening. Molecules. 2019. 24(24): 4428.
