A5089122732- Epigenetics and DNA Methylation
- RNA modifications and cancer
- Crystallization and Solubility Studies
- Cancer-related gene regulation
- X-ray Diffraction in Crystallography
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Biotin and Related Studies
- Protein Structure and Dynamics
- Click Chemistry and Applications
- Ubiquitin and proteasome pathways
- Synthesis and Biological Evaluation
- MicroRNA in disease regulation
- Computational Drug Discovery Methods
University of California, San Francisco
2019-2022
University of California, Berkeley
2019-2022
Pfizer (United States)
2014-2015
A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability thermodynamic solubility issues associated with previous lead compound 1. The incorporated an sp3 hybridized carbon atom at the 7-position lactam moiety present in 1 as a replacement for dimethylisoxazole group. This transformation enabled optimization physicochemical properties potency compared Analysis relationships between calculated log...
Sense and respond Many signaling pathways start with cellular proteins sensing responding to small molecules. Despite advances in protein design, creating a protein-based sense-and-respond system remains challenging. Glasgow et al. designed binding sites at the interface of heterodimers (see Perspective by Chica). By fusing each monomer one half split reporter, they linked ligand-driven dimerization reporter output. The computational design strategy provides generalizable approach create...
A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to dimethylpyridone moiety via an amide linkage has been designed. preferential torsion that improved the binding properties compounds was identified for this computational analysis. Cyclization linker resulted in six-membered lactam analogue, compound 18. This transformation significantly ligand efficiency/potency cyclized relative its acyclic analogue. Additional optimization...
SignificanceComputational protein design promises to advance applications in medicine and biotechnology by creating proteins with many new useful functions. However, functions require the of specific often irregular atom-level geometries, which remains a major challenge. Here, we develop computational methods that predict local geometries greater accuracy than existing methods. Then, as proof concept, leverage these conformations enzyme ketosteroid isomerase change protein's preference for...
Conformational remodeling of chromatin in cells is known to alter gene expression. The histone code hypothesis postulates that multiple modifications present on tails can regulate expression both through direct effects compaction as well recruitment unique complexes signal specific downstream functions. Histone methylation an important component the code, and dysregulation disease makes methyltransferases demethylases viable targets for drug discovery. We developed a biochemical assay...
ABSTRACT Sensing and responding to signals is a fundamental ability of living systems, but despite remarkable progress in computational design new protein structures, there no general approach for engineering arbitrary sensors. Here we describe generalizable strategy designing sensor/actuator proteins by building binding sites de novo into heterodimeric protein-protein interfaces coupling ligand sensing modular actuation via split reporters. Using this approach, designed sensors that respond...
Abstract Introduction: Histone methyltransferases (HMT's) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups from S-adenosyl-L-methionine (SAM) to lysine and arginine residues on histone proteins. This methylation results in changes gene expression. Over-expression misregulation these enzymes has been associated with cancer, making HMT's an attractive area for development new cancer therapeutics. We developed highly sensitive, high throughput...
ABSTRACT Accurate positioning of functional residues is critical for the design new protein functions, but has remained difficult because prevalence irregular local geometries in active sites. Here we introduce two computational methods that build from sequence with atomic accuracy: fragment kinematic closure (FKIC) and loophash (LHKIC). FKIC LHKIC integrate approaches: robotics-inspired kinematics backbones insertion peptide fragments, show up to 140-fold improvements native-like...