Kaushik, V. — Page 2 | Search bioRxiv

bioRxiv2021

Discovery of a first-in-class inhibitor of the PRMT5-substrate adaptor interaction

PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action and structure determination studies revealed that these compounds form a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts the PRMT5-RIOK1 complex, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive small molecule that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.

cancer biology↗

bioRxiv2020

Machine Learning Algorithms for Predicting Coronary Artery Disease: Efforts Toward an Open Source Solution

The development of Coronary Artery Disease (CAD), one of the most prevalent diseases in the world, is heavily influenced by several modifiable risk factors. Predictive models built using machine learning (ML) algorithms may assist healthcare practitioners in timely detection of CAD, and ultimately, may improve outcomes. In this study, we have applied six different ML algorithms to predict the presence of CAD amongst patients listed in an openly available dataset provided by the University of California Irvine (UCI) Machine Learning Repository, named "the Cleveland dataset." All six ML algorithms achieved accuracies greater than 80%, with the "Neural Network" algorithm achieving accuracy greater than 93%. The recall achieved with the "Neural Network" model is also highest of the six models (0.93). Additionally, five of the six algorithms resulted in very similar AUC-ROC curves. The AUC-ROC curve corresponding to the "Neural Network" algorithm is slightly steeper implying higher "true positive percentage" achieved with this model. We also extracted the variables of importance in the "Neural Network" model to help in the risk assessment. We have released the full computer code generated in this study in the public domain as a preliminary effort toward developing an open solution for predicting the presence of coronary artery disease in a given population and present a workflow model for implementing a possible solution.

bioinformatics↗