In silico identification of inhibitors targeting N-Terminal domain of human Replication Protein A

Publication date: Available online 20 October 2018Source: Journal of Molecular Graphics and ModellingAuthor(s): Süleyman Selim Çınaroğlu, Emel TimuçinAbstractReplication Protein A (RPA) mediates DNA Damage Response (DDR) pathways through protein-protein interactions (PPIs). Targeting the PPIs formed between RPA and other DNA Damage Response (DDR) mediators has become an intriguing area of research for cancer drug discovery. A number of studies applied different methods ranging from high throughput screening approaches to fragment-based drug design tools to discover RPA inhibitors. Although these methods are robust, virtual screening approaches may be allocated as an alternative to such experimental methods, especially for screening of large libraries. Here we report the comprehensive screening of the large database, ZINC15 composed of ∼750 M compounds and the comparison of the identified ligands with the previously known inhibitors by means of binding affinity and drug-likeness. Initially, a ligand library sharing similarity with a promising inhibitor of the N-terminal domain of the RPA70 subunit (RPA70N) was generated by screening of the ZINC15 library. 46,999 ligands were collected and screened by LeDock which produced a satisfactory correlation with the experimental values (R2 = 0.77). 10 of the top-scoring ligands in LeDock were directly progressed to molecular dynamics (MD) simulations, while 10 additional ligands were also selected based on their LeDock sco...
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research