SAMPL7 protein-ligand challenge: A community-wide evaluation of computational methods against fragment screening and pose-prediction.

A novel crystallographic fragment screening data set was generated and used in the SAMPL7 challenge for protein-ligands. The SAMPL challenges prospectively assess the predictive power of methods involved in computer-aided drug design. Application of various methods to fragment molecules are now widely used in the search for new drugs. However, there is little in the way of systematic validation specifically for fragment-based approaches. We have performed a large crystallographic high-throughput fragment screen against the therapeutically relevant second bromodomain of the Pleckstrin-homology domain interacting protein (PHIP2) that revealed 52 different fragments bound across 4 distinct sites, 47 of which were bound to the pharmacologically relevant acetylated lysine (Kac) binding site. These data were used to assess computational screening, binding pose prediction and follow-up enumeration. All submissions performed randomly for screening. Pose prediction success rates (defined as less than 2 Å root mean squared deviation against heavy atom crystal positions) ranged between 0 and 25% and only a very few follow-up compounds were deemed viable candidates from a medicinal-chemistry perspective based on a common molecular descriptors analysis. The tight deadlines imposed during the challenge led to a small number of submissions suggesting that the accuracy of rapidly responsive workflows remains limited. In addition, the application of these methods to reproduce crystallographic fragment data still appears to be very challenging. The results show that there is room for improvement in the development of computational tools particularly when applied to fragment-based drug design.

circPHIP promotes oral squamous cell carcinoma progression by sponging miR-142-5p and regulating PHIP and ACTN4 expression.

Circular RNA (circRNA) is a newly discovered class of noncoding RNAs that plays key regulatory role in pathological development, including the regulation of several solid tumors. However, the effects of circRNA expression on oral squamous cell carcinoma (OSCC) remain unclear. With the use of high-throughput RNA sequencing data on eight paired oral cancer and adjacent healthy tissues, we observed that circRNA derived from the gene encoding pleckstrin homology domain-interacting protein (circPHIP) was highly expressed in OSCC. Additionally, circPHIP was highly expressed in other OSCC-related cell lines and was associated with tumor metastasis, TNM stage, and human papilloma virus infection status. The inhibition of circPHIP expression reduced OSCC cell migration, invasion, and proliferation. We found that circPHIP could adsorb microRNA (miR)-142-5p and upregulate the expression of PHIP and alpha-actinin 4 (ACTN4), both of which are potential oncogenes closely related to OSCC prognosis. The inhibition of miR-142-5p or overexpressing PHIP or ACTN4 reversed the circPHIP depletion-induced attenuation of OSCC malignancy. In conclusion, circPHIP is overexpressed in OSCC and enhances its malignancy via an miR-142-5p/PHIP-ACTN4/AKT serine/threonine kinase 1 signaling axis. Therefore, circPHIP may represent a novel target for treating OSCC.