A5100750182- Parkinson's Disease Mechanisms and Treatments
- Plant Gene Expression Analysis
- Cholinesterase and Neurodegenerative Diseases
- Photochromic and Fluorescence Chemistry
- Crystallography and molecular interactions
- Computational Drug Discovery Methods
- Advanced Materials and Mechanics
- Graphene and Nanomaterials Applications
- Surfactants and Colloidal Systems
- Plant biochemistry and biosynthesis
- Molecular Sensors and Ion Detection
- Viral Infectious Diseases and Gene Expression in Insects
- Synthetic Organic Chemistry Methods
- Delphi Technique in Research
- Spectroscopy Techniques in Biomedical and Chemical Research
- Carbon and Quantum Dots Applications
- Polymer Surface Interaction Studies
- Synthesis and Properties of Aromatic Compounds
- Liver Disease Diagnosis and Treatment
- Liquid Crystal Research Advancements
- X-ray Diffraction in Crystallography
- Inhalation and Respiratory Drug Delivery
- Biotechnology and Related Fields
- Plant Disease Resistance and Genetics
- Hepatocellular Carcinoma Treatment and Prognosis
Merck & Co., Inc., Rahway, NJ, USA (United States)
2020-2024
Hebei University of Technology
2024
Hebei Petroleum University of Technology
2024
Peking University First Hospital
2023
Peking University
2023
Jiangsu Vocational College of Medicine
2019-2022
University of Macau
2022
Jinan University
2021
Shaanxi Normal University
2021
Yale University
2014-2018
The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling progressive neurodegenerative disorder whose current therapies are limited in scope efficacy. In this report, we describe rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated the discovery of brain-penetrant, candidate-quality molecules as represented compounds 22 24. These exhibit remarkable selectivity against...
The atomic point-charge model used in most molecular mechanics force fields does not represent well the electronic anisotropy that is featured many directional noncovalent interactions. Sulfur participates several types of such interactions with its lone pairs and σ-holes. current study develops a new model, via addition off-atom charged sites, for variety sulfur compounds OPLS-AA OPLS/CM5 to address lack charge anisotropy. Parameter optimization carried out reproduce liquid-state...
Two orthogonal approaches for hit identification in drug discovery are large-scale vitro and silico screening. In recent years, due to the emergence of new targets a rapid increase size readily synthesizable chemical space, there is growing emphasis on integration two techniques improve finding efficiency. Here, we highlight three examples projects at Merck & Co., Inc., Kenilworth, NJ, USA which different virtual screening (VS) techniques, each specifically tailored leverage knowledge...
Inhibition of leucine-rich repeat kinase 2 is a genetically supported mechanism for the treatment Parkinson's disease. We previously disclosed discovery an indazole series lead that demonstrated both safety and translational risks. The risks were hypothesized to be unknown origin, so structural diversity in subsequent chemical matter was prioritized. identified due low brain Kp
Halogen bonding, due to its directionality and tunable strength, is being increasingly utilized in self-assembling materials crystal engineering. Using density functional theory (DFT) molecular mechanics (OPLS/CM1Ax) calculations, multiply halogen bonded complexes of brominated imidazole pyridine are investigated along with their potential construction architectures. Dimers 1-10 bonds considered reveal maximal binding energies 3-36 kcal/mol. Cooperative (nonadditive) effects found that...
It is widely accepted that structural rigidity required to achieve high levels of asymmetric induction in catalytic, enantioselective reactions. This fundamental design principle often does not apply highly selective catalytic peptides exhibit conformational heterogeneity. As a result, these complex systems are particularly challenging study both experimentally and computationally. Herein, we utilize molecular dynamics simulations investigate the role mobility on reactivity selectivity...
Inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents a genetically supported, chemically tractable, and potentially disease-modifying mechanism to treat Parkinson's disease. Herein, we describe the optimization novel series potent, selective, central nervous system (CNS)-penetrant 1-heteroaryl-1H-indazole type I (ATP competitive) LRRK2 inhibitors. Type ATP-competitive physicochemical properties were integrated with CNS drug-like through combination structure-based drug...
Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid efficacious disease-modifying therapies. Herein, we describe invention an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, property-based drug design in concert rigorous application silico calculations presynthesis predictions enabled prioritization molecules...
Triclocarban (TCC), as a broad spectrum antibacterial agent widely used in personal care products, has recently been recognized environmental pollutant with the potential of adversely affecting wildlife and human health. However, behavior TCC blood circulatory system toxicity at molecular level have poorly investigated. In this study, effect on serum albumin (HSA) binding mechanism to HSA were examined using spectroscopic techniques modeling methods. The fluorescence results suggested that...
The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe and evolution a picolinamide-derived lead series. Our initial optimization efforts aimed at improving potency CLK2 off-target selectivity compound 1 by modifying heteroaryl C-H hinge linker regions. This resulted in 12 which advanced deep into our operating plan (ROP) before aniline metabolite...
Intratumor microbiomes can influence tumorigenesis and progression. The relationship between intratumor cervical cancer metastasis, however, remains unclear.
Due to the importance of water in chemical and biological systems, a coarse-grained representation solvent can greatly simplify description system while retaining key thermodynamic properties medium. A multiscale solvation model that couples all-atom solutes polarizable Martini (AAX/CGS) is developed reproduce free energies hydration organic solutes. Using Monte Carlo/free energy perturbation (MC/FEP) calculations, results from simulations are compared. Improved accuracy obtained with...
As a pathogenic toxin, endotoxins are the culprit for endotoxemia and can be generally removed from blood by hemoperfusion. Reduced graphene oxide (rGO) is promising endotoxin sorbent hemoperfusion owing to its excellent adsorption capacity, but it has side effect of nonspecific low compatibility. Polymyxin B (PMB) acts as an organic affinity ligand that specifically bind endotoxins. natural anticoagulant, heparin (Hep) reduce risk coagulation improve compatibility materials. Herein, rGO...
Big data in health care has gained popularity recent years for disease prediction. Breast cancer infections are the most common urban Indian women, as well women internationally, and impacted by many events across countries regions. malignant growth is a notable among women. According to WHO, it represents 14% of all tumors A couple studies have been directed utilizing big foresee breast growth. causing transformation healthcare, with better more ideal results. Monstrous volumes...
Objective To explore the curriculum setting of traditional Chinese medicine (TCM) nursing practice, and to provide a theoretical reference for TCM training in communities ClassⅡ ClassⅢ hospitals. Methods The entries practice courses were developed by literature review, group discussion Delphi expert enquiry between January 2016 June 2017. Results The collection rate questionnaires during two rounds was 100% 80%, respectively. The authority coefficient (Cr) 0.86 0.84, Kendall...