Dual-electron-enhanced effect in K-doped MoS few layers for high electrocatalytic activity as the counter electrode in dye-sensitized solar cells.

Designing counter electrodes (CEs) with high efficiency and understanding the mechanism of dye-sensitized solar cells (DSSCs) are still challenges. In this paper, we synthesized K-doped molybdenum disulfide (K-MoS) with few layers and it has a great enhancement effect on the electrocatalytic activity compared to pure MoS CE and reference Pt CE. A dual electron-path model is proposed to explain the mechanism, which is supported by first-principles calculations.

Discovery of Isoindoline Amide Derivatives as Potent and Orally Bioavailable ADAMTS-4/5 Inhibitors for the Treatment of Osteoarthritis.

Osteoarthritis (OA) treatment is a highly unmet medical need. Development of a disease-modifying OA drug (DMOAD) is challenging with no approved drugs on the market. Inhibition of ADATMS-4/5 is a promising OA therapeutics to target cartilage degradation and potentially can reduce joint pain and restore its normal function.

Discovery of novel spiro compound as RAF kinase inhibitor with in vitro potency against KRAS mutant cancer.

The development of RAF inhibitors targeting cancers with wild type RAF kinase and/or RAS mutation has been challenging due to the paradoxical activation of the RAS-RAF-MEK-ERK cascade following RAF inhibitor treatment. Herein is the discovery and optimization of a series of RAF inhibitors with a novel spiro structure. The most potent spiro molecule 9 showed excellent in vitro potency against b/c RAF enzymes and RAS mutant H358 cancer cells with minimal paradoxical RAF signaling activation.

Discovery of spiro amide SHR902275: A potent, selective, and efficacious RAF inhibitor targeting RAS mutant cancers.

The RAS-RAF-MEK-ERK signaling pathway plays a key role to regulate multiple cellular functions. Acquired resistance to the first-generation RAF inhibitors that only targeted the bRAF mutation prompted the need for a new generation of RAF inhibitors to target cancers bearing mutant RAS and wild type RAF activity by inhibition of paradoxical activation. Starting from the company's previously reported RAF inhibitor 1, extensive drug potency and drug-like properties optimizations led to the discovery of molecule 33 (SHR902275) with greatly improved in vitro potency and solubility.

Protein-Ligand Empirical Interaction Components for Virtual Screening.

A major shortcoming of empirical scoring functions is that they often fail to predict binding affinity properly. Removing false positives of docking results is one of the most challenging works in structure-based virtual screening. Postdocking filters, making use of all kinds of experimental structure and activity information, may help in solving the issue.

Interaction Entropy for Computational Alanine Scanning.

The theoretical calculation of protein-protein binding free energy is a grand challenge in computational biology. Accurate prediction of critical residues along with their specific and quantitative contributions to protein-protein binding free energy is extremely helpful to reveal binding mechanisms and identify drug-like molecules that alter protein-protein interactions. In this paper, we propose an interaction entropy approach combined with the molecular mechanics/generalized Born surface area (MM/GBSA) method for solvation to compute residue-specific protein-protein binding free energy.