iPPI-DB: an online database of modulators of protein-protein interactions

Abstract

In order to boost the identification of low-molecular-weight drugs on protein-protein interactions (PPI), it is essential to properly collect and annotate experimental data about successful examples. This provides the scientific community with the necessary information to derive trends about privileged physicochemical properties and chemotypes that maximize the likelihood of promoting a given chemical probe to the most advanced stages of development. To this end we have developed iPPI-DB (freely accessible at http://www.ippidb.cdithem.fr), a database that contains the structure, some physicochemical characteristics, the pharmacological data and the profile of the PPI targets of several hundreds modulators of protein-protein interactions. iPPI-DB is accessible through a web application and can be queried according to two general approaches: using physicochemical/pharmacological criteria; or by chemical similarity to a user-defined structure input. In both cases the results are displayed as a sortable and exportable datasheet with links to external databases such as Uniprot, PubMed. Furthermore each compound in the table has a link to an individual ID card that contains its physicochemical and pharmacological profile derived from iPPI-DB data. This includes information about its binding data, ligand and lipophilic efficiencies, location in the PPI chemical space, and importantly similarity with known drugs, and links to external databases like PubChem, and ChEMBL.

Figure 1.

Example of a query on iPPI-DB using the mode ‘Chemical Similarity’. As the query compound, the user can either copy and paste a SMILES string into the interface, or directly sketch the compound within a Marvin JS editor. Here, we show an example with the structure with a recently identified piperidinone-based inhibitor of the MDM2/p53 interaction (25). Then, the compound can properly be imported, and the desired type of fingerprints for the chemical similarity search has to be chosen between ECFP4 and FCFP4. The search provides the user with all the binding data (here 47) of the 20 most similar iPPI-DB compounds in a table that can be sorted according to various criteria: molecular descriptors, activity, efficiencies or bibliographic IDs. The interface also provides a summary of the properties of the input compound using a radar chart based on nine physicochemical properties (molecular weight–MW, hydrophobicity–AlogP, the number of H-bond donors–HBD and acceptors–HBA, Topological Polar Surface Area–TPSA, the number of rotatable bonds RB, the number of aromatic rings–Ar, the proportion of sp3 carbon atoms–Fsp3 and the number of chiral centers–R/S) and its compliance to the three chemistry rules, Lipinski's RO5, Veber's and Pfizer's 3/75.

Figure 2.

iPPI-DB ID card of compound 682. All data available of a given compound (here compound 682 as the first hit on the chemical similarity search from Figure 1) are provided through four different tabs: compound summary, physicochemistry, pharmacology and drug similarity.