Protein-protein interactions (PPI) 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 serine PPI targeted libraries to generate structurally-diverse small-molecule screening compounds by employing a virtual molecular screening method.
Figure 1. The constructed protein-protein interaction (PPI) network. (Coppini, R.; et al. 2019)
Receptor-based PPI Targeted Library Design
To cover relevant chemical space that includes peptidomimetic molecules, our libraries are not made compliant with Lipinski's Rule of Five. Each screening subset contains drug-like screening compounds free of PAINS, toxic, and reactive groups that are potential PPI binders. The following PPI-related molecular targets are aimed:
Bcl-2 is a family of proteins associated with evolution. There are 25 known genes in the Bcl-2 family, and these proteins control the mitochondrial outer membrane permeability (MOMP) and are able to be pro-apoptotic (Bax, Bad, Bak and Bok, etc.) or anti-apoptotic (including Bcl-2 proper, Bcl-xl and Bcl-w, etc.). BOC Sciences has designed a Bcl2-PPI inhibitors library to provide anti-apoptotic BCL-2 family proteins, which are helpful in inducing apoptosis of cancer cells
p53, encoded by the oncogene TP53, is one of the most important oncogenic factors in vivo. p53 is negatively regulated by MDM2/MDM4 through a p53-MDM2/MDM4 negative feedback loop. In recent years, p53-related drug development has been a hot topic in oncology research, and we are committed to designing a reliable MDM2-p53 interaction inhibitors library to support the development of p53-related antitumor drugs
Intercellular cell adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin superfamily (IGSF) of adhesion molecules and is an important adhesion molecule that mediates the adhesion response. ICAM-1 exerts its biological activity by binding to specific receptors on the surface of VECs. As a transmembrane protein of leukocytes and endothelial cells, ICAM1 plays an important role in stabilizing intercellular interactions, and facilitating migration of leukocytes and endothelial cells. Small molecules that disrupt this interaction by binding to the anti-apoptotic BCL-2 family proteins have been designed to induce apoptosis of cancer cells
Integrins are a family of transmembrane glycoprotein signaling receptors that can transmit biological information bidirectionally across the plasma membrane. Integrin αIIbβ3 is highly expressed in platelets and their progenitor cells, and plays a central role in platelet function, hemostasis and arterial thrombosis. Integral protein αIIbβ3 is also involved in cancer progression, such as tumor cell proliferation and metastasis. Therefore, integral αIIbβ3 and its signaling pathway are considered as promising targets for antithrombotic therapy
Inhibitors of apoptosis (IAP) are a family of functionally and structurally related proteins that act as endogenous inhibitors of programmed cell death (apoptosis). The best characterized IAP is XIAP, which binds cystathione-9, cystathione-3 and cystathionase 7, thereby inhibiting their activation and preventing apoptosis. At BOC Sciences, efforts to target the IAP proteins have focused on the design of small molecules that mimic the binding of the endogenous IAP antagonist second mitochondria-derived activator of caspases/direct IAP-binding protein
- Elastase
Elastases are simple digestive proteases in the intestine, and belong to the classes of serine proteases, cysteine proteases and metalloproteases. Mammalian elastases are found mainly in the pancreas and phagocytes. Among the non-mammalian elastases, a variety of serine elastases are present. Elastases play a pathological role in emphysema, cystic fibrosis, infection, inflammation and atherosclerosis
BET family proteins are important epigenetic regulatory proteins and transcriptional regulatory proteins, which are important for normal cell growth and cell cycle. Downstream genes of BET family member BRD4, such as MYC, CDK and BCL2, play important roles in tumorigenesis and development, therefore BRD4-targeted drugs are expected to be a anti-cancer targeted drug
There are four members of BET family proteins, namely BRD2, BRD3, BRD4 and BRDT, of which BRD4 has three different forms of shedders. In addition to the ability to bind acetylated histones through the BRD domain, BRD4 can also form protein complexes with other proteins such as P-TEFb and Mediator
Figure 2. The ligand druggability relative to the protein pocket druggability for PPI drugs/candidates. (Shin, W. H.; et al. 2020)
Receptor-based PPI Targeted 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 Receptor-based PPI Targeted Library design at competitive prices for global customers. Personalized and customized services of Receptor-based PPI Targeted 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
- Qi, F.; et al. Bioinformatics analysis of high-throughput data to validate potential novel biomarkers and small molecule drugs for glioblastoma multiforme. The Journal of international medical research. 2020. 48(7): 030006052092454.
- Shin, W. H.; et al. Current Challenges and Opportunities in Designing Protein–Protein Interaction Targeted Drugs. Advances and Applications in Bioinformatics and Chemistry. 2020. 13: 11-25.
