Katrina W Lexa

Katrina W Lexa
University of California, San Francisco | UCSF · Department of Pharmaceutical Chemistry

PhD

About

33
Publications
4,808
Reads
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1,124
Citations
Additional affiliations
August 2011 - present
University of California, San Francisco
Position
  • PostDoc Position
August 2006 - August 2011
University of Michigan
May 2002 - August 2006
Hamilton College

Publications

Publications (33)
Article
Ticks transmit a diverse array of microbes to vertebrate hosts, including human pathogens, which has led to a human-centric focus in this vector system. Far less is known about pathogens of ticks themselves. Here, we discover that a toxin in blacklegged ticks (Ixodes scapularis) horizontally acquired from bacteria—called domesticated amidase effect...
Preprint
Full-text available
Hard ticks interface with diverse microbes while feeding on vertebrate hosts. We previously discovered that ticks horizontally acquired an antimicrobial toxin gene from bacteria known as domesticated amidase effector 2 ( dae2 ). Here we show that this effector from the tick disease vector Ixodes scapularis (Dae2 Is ) is delivered to the host bite s...
Article
Full-text available
Quantitative structure-activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the as...
Article
A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, includin...
Article
Full-text available
Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful tran...
Article
Macrocycles are appealing drug candidates due to their high-affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosoma...
Article
Rationale: During the development of a novel synthetic route to doravirine; (1), a human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI), an unanticipated reaction intermediate, methyl (Z)-2-(3-chloro-5-cyanophenoxy)-5-(3-(3-chloro-5-cyanophenoxy)-2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-5-ethoxy-3-(tr...
Article
An unusual in-source fragmentation pattern observed for 14 doubly quaternized cinchona alkaloid-based phase-transfer catalysts (PTC) was studied using (+)-ESI high resolution mass spectrometry. Loss of the substituted benzyl cation (R1 or R2) was found to be the major product ion [M²⁺ – R1⁺ or R2⁺]⁺ in MS spectra of all PTC compounds. A Hofmann eli...
Article
Natural product and synthetic macrocycles are chemically and topologically diverse. An efficient, accurate, and general method for generating macrocycle conformations would enable structure-based design of macrocycle drugs or host-guest complexes. Computational sampling also provides insight into transiently populated states, complementing crystall...
Article
Mixed-solvent molecular dynamics (MixMD) simulations use full protein flexibility and competition between water and small organic probes to achieve accurate hot-spot mapping on protein surfaces. In this study, we improved MixMD using HIV-1 protease as the test case. We used three probe-water solutions (acetonitrile-water, isopropanol-water, and pyr...
Article
Full-text available
Many cyclic peptide natural products are larger and structurally more complex than conventional small molecule drugs. Although some molecules in this class are known to possess favorable pharmacokinetic properties, there have been few reports on the membrane permeabilities of cyclic peptide natural products. Here, we present the passive membrane pe...
Article
Cyclic peptide natural products contain a variety of conserved, non-proteinogenic structural elements such as D-amino acids and amide N-methylation. In addition, many cyclic peptides incorporate γ-amino acids and other elements derived from polyketide synthases. We hypothesized that the position and orientation of these extended backbone elements i...
Article
Full-text available
Objective To determine the cause and course of a novel syndrome with progressive encephalopathy and brain atrophy in children.Methods Clinical whole-exome sequencing was performed for global developmental delay and intellectual disability; some patients also had spastic paraparesis and evidence of clinical regression. Six patients were identified w...
Article
Probe mapping is a common approach for identifying potential binding sites in structure-based drug design; however, it typically relies on energy minimizations of probes in the gas phase and a static protein structure. The mixed-solvent molecular dynamics (MixMD) approach was recently developed to account for full protein flexibility and solvation...
Article
Full-text available
One of the many factors involved in determining the distribution and metabolism of a compound is the strength of its binding to human serum albumin. While experimental and QSAR approaches for determining binding to albumin exist, various factors limit their ability to provide accurate binding affinity for novel compounds. Thus, to complement the ex...
Article
Computational approaches to fragment-based drug design (FBDD) can complement experiments and facilitate the identification of potential hot spots along the protein surface. However, the evaluation of computational methods for mapping binding sites frequently focuses upon the ability to reproduce crystallographic coordinates to within a low RMSD thr...
Article
Full-text available
The target range of a bacterial secretion system can be defined by effector substrate specificity or by the efficacy of effector delivery. Here, we report the crystal structure of Tse1, a type VI secretion (T6S) bacteriolytic amidase effector from Pseudomonas aeruginosa. Consistent with its role as a toxin, Tse1 has a more accessible active site th...
Article
Structure-based drug design has become an essential tool for rapid lead discovery and optimization. As available structural information has increased, researchers have become increasingly aware of the importance of protein flexibility for accurate description of the native state. Typical protein-ligand docking efforts still rely on a single rigid r...
Article
This Erratum is to declare that the values reported for R2 in the paper are actually Pearson R values. The wrong column of data in a spreadsheet was used inadvertently. All correlation values in the paper are correct, just mislabeled with the squared superscript. One of the major conclusions noted in the abstract and discussed in the “Strengths and...
Article
A major goal in drug design is the improvement of computational methods for docking and scoring. The Community Structure Activity Resource (CSAR) aims to collect available data from industry and academia which may be used for this purpose ( www.csardock.org ). Also, CSAR is charged with organizing community-wide exercises based on the collected dat...
Article
A recent crystal structure of HIV-1 protease (HIVp) was the first to experimentally observe a ligand targeting an open-flap conformation. Researchers studying a symmetric pyrrolidine inhibitor found that two ligands cocrystallized with the protease, forcing an unusual configuration and unique crystallographic contacts. One molecule is centered in t...
Article
Structure-based drug design (SBDD) is defined as the use of three-dimensional structural data to advance lead development and optimization studies. Many SBDD projects have used a rigid protein structure to represent the receptor target in order to gain greater throughput with minimal computational time. However, numerous studies have illustrated th...
Article
A traditional technique for structure-based drug design (SBDD) is mapping of protein surfaces with probe molecules to identify "hot spots" where key functional groups can best complement the receptor. Common methods, such as minimization of probes or calculation of grids, use a fixed protein structure in the gas phase, ignoring both protein flexibi...
Article
Full-text available
The goals of this article are to (1) provide further validation of the Glycam06 force field, specifically for its use in implicit solvent molecular dynamic (MD) simulations, and (2) to present the extension of G.N. Ramachandran's idea of plotting amino acid phi and psi angles to the glycosidic phi, psi, and omega angles formed between carbohydrates...
Article
The 1TW7 crystal structure of HIV-1 protease shows the flaps placed wider and more open than what is seen in other examples of the semi-open, apo form. It has been proposed that this might be experimental evidence of allosteric control, because crystal packing creates contacts to the "elbow region" of the protease, which may cause deformation of th...
Article
Full-text available
Breast cancer is the most common cancer among women. Tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment, yet many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Therefore, scientists are searching for breast cancer drugs that have different molecular targets. Pre...
Article
Full-text available
Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets....

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