A5026656308- Melanoma and MAPK Pathways
- Cancer Mechanisms and Therapy
- Synthesis and biological activity
- Computational Drug Discovery Methods
- Cytokine Signaling Pathways and Interactions
- Protein Kinase Regulation and GTPase Signaling
- Chemical Synthesis and Analysis
- Synthesis and Characterization of Heterocyclic Compounds
- Innovative Microfluidic and Catalytic Techniques Innovation
- Phytochemical compounds biological activities
- Organic Chemistry Cycloaddition Reactions
- Cholinesterase and Neurodegenerative Diseases
- Oxidative Organic Chemistry Reactions
- Protein Structure and Dynamics
- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Antibiotic Resistance in Bacteria
- Crystallography and molecular interactions
- Epigenetics and DNA Methylation
- Asymmetric Synthesis and Catalysis
- X-ray Diffraction in Crystallography
- Cancer-related gene regulation
- Chemical Reaction Mechanisms
- Receptor Mechanisms and Signaling
- Liver physiology and pathology
Arrien Pharmaceuticals (United States)
2020-2021
Recursion (United States)
2020-2021
Novartis (United States)
2008-2020
Novartis (Switzerland)
2014-2015
Novartis Institutes for BioMedical Research
2014
Pathways Behavioral Services
2014
GlaxoSmithKline (United Kingdom)
2002-2010
University of Sheffield
2005
New Frontier
2005
University of California, Berkeley
2002
Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which these best complements the site. An evaluation 10 docking programs and 37 was conducted against eight proteins seven types for three tasks: mode prediction, virtual screening lead identification, rank-ordering by affinity optimization. All were able generate ligand similar crystallographically determined protein/ligand complex structures at...
Abstract Purpose: PIM kinases have been shown to act as oncogenes in mice, with each family member being able drive progression of hematologic cancers. Consistent this, we found that PIMs are highly expressed human cancers and show isoform has a distinct expression pattern among disease subtypes. This suggests inhibitors all three would be effective treating multiple malignancies. Experimental Design: Pan-PIM proven difficult develop because PIM2 low Km for ATP and, thus, requires very...
The discovery of inhibitors targeting novel allosteric kinase sites is very challenging. Such compounds, however, once identified could offer exquisite levels selectivity across the kinome. Herein we report our structure-based optimization strategy a dibenzodiazepine hit 1, discovered in fragment-based screen, yielding highly potent and selective PAK1 such as 2 3. Compound was cocrystallized with to confirm binding an site reveal key interactions. 3 modulated at cellular level due its...
Medicinal chemists' "intuition" is critical for success in modern drug discovery. Early the discovery process, chemists select a subset of compounds further research, often from many viable candidates. These decisions determine campaign, and ultimately what kind drugs are developed marketed to public. Surprisingly little known about cognitive aspects decision-making when they prioritize compounds. We investigate 1) how extent simplify problem identifying promising compounds, 2) whether agree...
Pan proviral insertion site of Moloney murine leukemia (PIM) 1, 2, and 3 kinase inhibitors have recently begun to be tested in humans assess whether pan PIM inhibition may provide benefit cancer patients. Herein, the synthesis, vitro activity, vivo activity an acute myeloid xenograft model, preclinical profile potent selective inhibitor compound 8 (PIM447) are described. Starting from reported aminopiperidyl 3, a strategy improve microsomal stability was pursued resulting identification...
The p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases is expressed in a variety cancers and its substrate phosphorylation has been implicated direct regulation cell survival, proliferation, polarity. This study characterizes presents the most selective potent RSK inhibitors known to date, LJH685 LJI308. Structural analysis confirms binding RSK2 N-terminal ATP-binding site reveals that inhibitor adopts an unusual nonplanar conformation explains excellent selectivity for...
While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, full understanding of this restricted by lack highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor N-terminal RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted optimized difluorophenol pyridine inhibitors RSK demonstrated cellularly inhibition YB1 phosphorylation. These...
PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 histone H3, leading to chromatin compaction repression tumor suppressor genes. Inhibiting this activity by small molecules targeting was shown result antitumor efficacy. Here, we describe the optimization chemical series representing new class inhibitors which acts allosterically via trimethyllysine pocket...
The acid–base dissociation constant, pKa, is a key parameter to define the ionization state of compound and directly affects its biopharmaceutical profile. In this study, we developed novel approach for pKa prediction using rooted topological torsion fingerprints in combination with five machine learning (ML) methods: random forest, partial least squares, extreme gradient boosting, lasso regression, support vector regression. With large diverse set 14 499 experimental values, models were...
Artificial intelligence (AI) is becoming established in drug discovery. For example, many the industry are applying machine learning approaches to target discovery or optimize compound synthesis. While our organization certainly these sorts of approaches, we propose an additional approach: using AI augment human intelligence. We have been working on a series recommendation systems that take advantage existing laboratory processes, both wet and computational, order provide inspiration...
The discovery and development of new antibiotics capable curing infections due to multidrug-resistant pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance our global healthcare system. Part broad program at Novartis address this urgent, unmet need includes the search for agents that inhibit novel bacterial targets. Here we report hit-to-lead optimization inhibitors phosphopantetheine adenylyltransferase (PPAT) from bacteria. Utilizing fragment-based...
Monobactam antibiotic 1 is active against Gram-negative bacteria even though it has a higher molecular weight (MW) than the limit of 600 Da typically applied in designing such compounds. On basis 2D NMR data, compound able to adopt compact conformation. The dimensions, projection area, and dipole moment derived from this conformation are compatible with porin permeation, as locations polar groups upon superimposition crystal structure ampicillin bound E. coli OmpF porin. Minimum inhibitory...
A ligand-based 3D pharmacophore model for serine/threonine kinase CDC7 inhibition was created and successfully applied in the discovery of novel 2-(heteroaryl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-ones. The provided a hypothesis lead generation missed by docking to homology model. Medicinal chemistry exploration series revealed clear structure–activity relationships consistent with pointed further optimization opportunities.
Reaction pathways of the Corey-Chaykovsky epoxidation reaction have been compared quantum chemically. Of concerted, torsional rotation and anti addition latter two were found to be favored both in gas phase CH(2)Cl(2) a model system. Several theoretically previously uncharacterized stationary points located, selective solvent effects observed. On pathway C-C bond formation transition state A, suitably substituted allow comparison with published experimental data, was able predict absolute...
Communication of data and ideas within a medicinal chemistry project on global as well local level is crucial aspect in the drug design cycle. Over time frame eight years, we built optimized FOCUS, platform to produce, visualize, share information various aspects discovery such cheminformatics, analysis, structural information, design. FOCUS tightly integrated with internal services that involve-among others-data retrieval systems in-silico models provides easy access automated modeling...