A5074126073- Bioactive natural compounds
- Natural product bioactivities and synthesis
- Biological Activity of Diterpenoids and Biflavonoids
- Crystallization and Solubility Studies
- Traditional and Medicinal Uses of Annonaceae
- X-ray Diffraction in Crystallography
- Phytochemistry and Biological Activities
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Plant chemical constituents analysis
- Ubiquitin and proteasome pathways
- Synthesis of Indole Derivatives
- Hepatitis C virus research
- Chemical Synthesis and Analysis
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Multiple Myeloma Research and Treatments
- Lipoproteins and Cardiovascular Health
- Plant Toxicity and Pharmacological Properties
- Alkaloids: synthesis and pharmacology
- Machine Learning in Materials Science
- Phytochemistry and Bioactive Compounds
- Synthesis and Biological Activity
- Biological and pharmacological studies of plants
- HIV/AIDS drug development and treatment
Uppsala University
2019-2024
University of Nairobi
2014-2020
Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies find main protease ultralarge chemical libraries. First, structure-based docking was used screen a diverse library 235 million compounds against active site. One hundred top-ranked were tested binding enzymatic assays. Second, fragment discovered by...
Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies VHL-based (1), which is permeable despite having high molecular weight and polarity large number rotatable bonds. We found that 1 populates elongated polar conformations solutions...
Proteolysis-targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, outer limits oral druggable space. We used NMR spectroscopy and molecular dynamics (MD) simulations independently gain insights into origin differences permeability displayed by three flexible cereblon having closely related structures. Both methods revealed that propensity adopt folded...
A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it therefore essential to identify chemical space where orally bioavailable PROTACs are more likely be situated. this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on potential and limitations design tools. Subsequently, describe cutting-edge experimental,...
Macrocycles constitute superior ligands for targets that have flat binding sites but often require long synthetic routes, emphasizing the need property prediction prior to synthesis. We investigated scope and limitations of machine learning classification models regression predicting cell permeability a set denovo-designed, drug-like macrocycles. 2D-Based models, which are fast calculate, discriminated between macrocycles had low-medium high may be used as virtual filters in early drug...
Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties macrocycles than 2D descriptors. However, computational identification relevant conformations for is nontrivial. Herein, we report that Caco-2 cell permeability difference between a pair diastereomeric correlated with their solvent accessible polar surface area and radius gyration. The were calculated from macrocycles' solution-phase conformational ensembles independently...
The ability to adjust conformations in response the polarity of environment, i.e. molecular chameleonicity, is considered be important for conferring both high aqueous solubility and cell permeability drugs chemical space beyond Lipinski's rule 5. We determined conformational ensembles populated by antiviral asunaprevir, simeprevir, atazanavir daclatasvir polar (DMSO-d6 ) non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas first three showed large...
Three new (1–3) and six known rotenoids (5–10), along with three isoflavones (11–13), were isolated from the leaves of Millettia oblata ssp. teitensis. A glycosylated isoflavone (4), four (14–18), one chalcone (19) root wood extract same plant. The structures elucidated by NMR mass spectrometric analyses. absolute configuration chiral compounds was established a comparison experimental ECD VCD data those calculated for possible stereoisomers. This is first report on use to assign rotenoids....
The replica exchange molecular dynamics (REMD) simulation is demonstrated to readily predict the conformations of macrocyclic drug lorlatinib, as validated by solution NMR studies. In aqueous solution, lorlatinib adopts a conformer identical its target bound structure. This stabilized an extensive hydrogen bond network solvents. chloroform, populates two conformers with second one being less polar, which may contribute lorlatinib's ability cross cell membranes.
The CH2Cl2/MeOH (1:1) extract of the aerial parts Tephrosia subtriflora afforded a new flavanonol, named subtriflavanonol (1), along with known flavanone spinoflavanone B, and flavanonols MS-II (2) mundulinol. structures were elucidated by use NMR spectroscopy mass spectrometry. absolute configuration was determined based on quantum chemical ECD calculations. In antiplasmodial assay, compound 2 showed highest activity against chloroquine-sensitive Plasmodium falciparum reference clones (D6...
Four new flavones with modified prenyl groups, namely (E)-5-hydroxytephrostachin (1), purleptone (2), (E)-5-hydroxyanhydrotephrostachin (3), and terpurlepflavone (4), along seven known compounds (5-11), were isolated from the CH₂Cl₂/MeOH (1:1) extract of stem Tephrosia purpurea subsp. leptostachya, a widely used medicinal plant. Their structures elucidated on basis NMR spectroscopic mass spectrometric evidence. Some showed antiplasmodial activity against chloroquine-sensitive D6 strains...
The discovery of cell permeable and orally bioavailable von Hippel-Lindau (VHL) proteolysis targeting chimeras (PROTACs) is challenging as their structures locates them at, or beyond, the outer limits oral druggable space. We have designed a set nine VHL PROTACs found that linker had profound impact on passive permeability. Determination solution ensembles in nonpolar solvent revealed high permeability was correlated to ability adopt folded conformations low accessible 3D polar surface area....
In our search for new antiplasmodial agents, the CH₂Cl₂/CH₃OH (1:1) extract of roots Tephrosia aequilata was investigated, and observed to cause 100% mortality chloroquine-sensitive (3D7) strain Plasmodium falciparum at a 10 mg/mL concentration. From this three chalconoids, E-2',6'-dimethoxy-3',4'-(2'',2''-dimethyl)pyranoretrochalcone (1, aequichalcone A), Z-2',6'-dimethoxy-3',4'-(2'',2''-dimethyl)pyranoretrochalcone (2, B), 4''-ethoxy-3''-hydroxypraecansone B (3, C) pterocarpene,...
Five new compounds—rhodimer (1), rhodiflavan A (2), B (3), C (4), and rhodacarpin (5)—along with 16 known secondary metabolites, were isolated from the CH2Cl2–CH3OH (1:1) extract of roots Tephrosia rhodesica. They identified by NMR spectroscopic, mass spectrometric, X-ray crystallographic, ECD spectroscopic analyses. The crude compounds 2–5, 9, 15, 21 showed activity (100% at 10 μg IC50 = 5–15 μM) against chloroquine-sensitive (3D7) strain Plasmodium falciparum.
Two new biflavanones (1 and 2), three bichalconoids (3–5), 11 known flavonoid analogues (6–16) were isolated from the stem bark extract (CH3OH–CH2Cl2, 7:3, v/v) of Ochna holstii. The structures metabolites elucidated by NMR spectroscopic mass spectrometric analyses. crude evaluated for antibacterial activity against Bacillus subtilis (Gram-positive) Escherichia coli (Gram-negative) as well cytotoxicity MCF-7 human breast cancer cell line. holstiinone A (1) exhibited moderate B. with MIC...
The methanol root extract of Clerodendrum myricoides (Hochst.) Vatke afforded two new (1, 2) and known (3, 4) iridoid glycosides. structures the isolated compounds were established based on NMR, IR, UV MS data analyses. crude constituents assayed for antiviral activity against human respiratory syncytial virus (RSV) in laryngeal epidermoid carcinoma (HEp-2) cells. inhibited RSV infectivity at EC50 = 0.21 μg/ml, while it showed cytotoxicity HEp-2 cells with CC50 9 μg/ml. Compound 2 43.2%...
Two new prenylated dihydrochalcones (1,2) and eighteen known secondary metabolites (3−20) were isolated from the CH2Cl2-MeOH (1:1) extracts of roots, stem bark leaves Eriosema montanum Baker f. (Leguminosae). The structures compounds characterized by NMR, IR, UV spectroscopic mass spectrometric analyses. 5, 10, 11 13 confirmed single crystal X-ray diffraction. antibacterial activity crude constituents established against Gram-positive Gram-negative bacteria. Among tested compounds, 1–4 10...
The leaf extract of
The new isoflavonoid kirkinone A (1) and biflavonoid B (2) along with six known compounds (3–8) were isolated from the methanolic extract of root bark Ochna kirkii. identified by NMR spectroscopic mass spectrometric analyses. Out eight natural products, calodenin (4) lophirone (6) showed significant antibacterial activity against Gram-positive bacterium Bacillus subtilis MIC values 2.2 28 μM, cytotoxicity MCF-7 human breast cancer cell line EC50 219.3 19.2 respectively. crude exhibited at...
Understanding the conformational preferences of free ligands in solution is often necessary to rationalize structure-activity relationships drug discovery. Herein, we examine behavior an epimeric pair side-chain stapled peptides that inhibit FAD dependent amine oxidase lysine specific demethylase 1 (LSD1). The differ only at a single stereocenter, but display major difference binding affinity. Their Raman optical activity (ROA) spectra are most likely dominated by C-terminus, obscuring...
Abstract Three new compounds, the silphiperfolanol angelate ester umutagarananol ( 1 ), macrocyclic pyrrolizidine alkaloids umutagarinine A and B 2 – 3 five known secondary metabolites 4 8 ) were isolated from CH Cl −MeOH (1 : 1) extract of roots stem bark Solanecio mannii (Hook. f.) (Asteraceae). The compounds characterized by NMR IR spectroscopic, mass spectrometric analyses, whereas relative stereochemistry was established NAMFIS‐based combined computational solution analysis. Synthetic...
Proteolysis targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, outer limits oral druggable space. We used NMR spectroscopy and MD simulations independently gain insight into origin differences permeability displayed by three flexible cereblon having closely related structures. Both methods revealed that propensity adopt folded conformations with low solvent...
Background: In Kenya, several species of the genus Maytenus are used in traditional medicine to treat many diseases including malaria. this study, phytochemical constituents and extracts undata, M. putterlickioides, senegalensis heterophylla were evaluated determine compound/s responsible for antimalarial activity. Keywords: Antimalarial plants, antiplasmodial, cytotoxicity, marker compound, spp., phytomedicine, pristimerin.