Discovery of novel SOS1 inhibitors using machine learning.

Overactivation of the rat sarcoma virus (RAS) signaling is responsible for 30% of all human malignancies. Son of sevenless 1 (SOS1), a crucial node in the RAS signaling pathway, could modulate RAS activation, offering a promising therapeutic strategy for RAS-driven cancers. Applying machine learning (ML)-based virtual screening (VS) on small-molecule databases, we selected a random forest (RF) regressor for its robustness and performance. Screening was performed with the L-series and EGFR-related datasets, and was extended to the Chinese National Compound Library (CNCL) with more than 1.4 million compounds. In addition to a series of documented SOS1-related molecules, we uncovered nine compounds that have an unexplored chemical framework and displayed inhibitory activity, with the most potent achieving more than 50% inhibition rate in the KRAS G12C/SOS1 PPI assay and an IC50 value in the proximity of 20 µg mL-1. Compared with the manner that known inhibitory agents bind to the target, hit compounds represented by CL01545365 occupy a unique pocket in molecular docking. An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors.

Physical Extraction and Feature Fusion for Multi-Mode Signals in a Measurement System for Patients in Rehabilitation Exoskeleton.

Measurement system of exoskeleton robots can reflect the state of the patient. In this study, we combined an inertial measurement unit and a visual measurement unit to obtain a repeatable fusion measurement system to compensate for the deficiencies of the single data acquisition mode used by exoskeletons. Inertial measurement unit is comprised four distributed angle sensors. Triaxial acceleration and angular velocity information were transmitted to an upper computer by Bluetooth. The data sent to the control center were processed by a Kalman filter to eliminate any noise. Visual measurement unit uses camera to acquire real time images and related data information. The two data acquisition methods were fused and have its weight. Comparisons of the fusion results with individual measurement results demonstrated that the data fusion method could effectively improve the accuracy of system. It provides a set of accurate real-time measurements for patients in rehabilitation exoskeleton and data support for effective control of exoskeleton robot.