A5087680450- Cancer-related Molecular Pathways
- Computational Drug Discovery Methods
- Machine Learning in Materials Science
- Protein Structure and Dynamics
- Click Chemistry and Applications
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- Enzyme Structure and Function
- Fluorine in Organic Chemistry
- Microbial Natural Products and Biosynthesis
- S100 Proteins and Annexins
- Metabolomics and Mass Spectrometry Studies
- DNA Repair Mechanisms
- Synthesis and Reactions of Organic Compounds
- Genetic factors in colorectal cancer
- Genomics and Chromatin Dynamics
- RNA Research and Splicing
- SARS-CoV-2 and COVID-19 Research
- Synthesis and Biological Evaluation
- Retinoids in leukemia and cellular processes
- Psoriasis: Treatment and Pathogenesis
- Synthesis and biological activity
- Angiogenesis and VEGF in Cancer
- Cancer Genomics and Diagnostics
Novartis (Switzerland)
2024
AstraZeneca (United Kingdom)
2020-2024
AstraZeneca (Sweden)
2021
AstraZeneca (Brazil)
2021
Broad Institute
2021
Harvard University
2021
MRC Laboratory of Molecular Biology
2012-2020
University of Tübingen
2010-2020
Berufsverband der Frauenärzte
2020
Medical Research Council
2016-2019
The application of molecular benchmarking sets helps to assess the actual performance virtual screening (VS) workflows. To improve efficiency structure-based VS approaches, selection and optimization various parameters can be guided by benchmarking. With DEKOIS 2.0 library, we aim further extend complement collection publicly available decoy sets. Based on BindingDB bioactivity data, provide 81 new structurally diverse benchmark for a wide variety different target classes. ensure meaningful...
Electrostatic interactions between small molecules and their respective receptors are essential for molecular recognition also key contributors to the binding free energy. Assessing electrostatic match of protein-ligand complexes therefore provides important insights into why ligands bind what can be changed improve binding. Ideally, ligand protein potentials at interaction interface should maximize complementarity while minimizing desolvation penalties. In this work, we present a fast...
The tumor suppressor p53 has the most frequently mutated gene in human cancers. Many of p53's oncogenic mutants are just destabilized and rapidly aggregate, targets for stabilization by drugs. We found certain 2-sulfonylpyrimidines, including one named PK11007, to be mild thiol alkylators with anticancer activity several cell lines, especially those mutationally compromised p53. PK11007 acted two routes: dependent independent. stabilized vitro via selective alkylation surface-exposed...
For widely applied in silico screening techniques success depends on the rational selection of an appropriate method. We herein present a fast, versatile, and robust method to construct demanding evaluation kits for objective (DEKOIS). This automated process enables creating tailor-made decoy sets any given bioactives. It facilitates target-dependent validation docking algorithms scoring functions helping save time resources. have developed metrics assessing improving set quality employ them...
Many cancers have the tumor suppressor p53 inactivated by mutation, making reactivation of mutant with small molecules a promising strategy for development novel anticancer therapeutics. The oncogenic mutation Y220C, which accounts approximately 100,000 cancer cases per year, creates an extended surface crevice in DNA-binding domain, destabilizes and causes denaturation aggregation. Here, we describe structure-guided design class small-molecule Y220C stabilizers challenging synthetic routes...
Aim:The p53 cancer mutation Y220C creates a conformationally unstable protein with unique elongated surface crevice that can be targeted by molecular chaperones.We report the structure-guided optimization of carbazole-based stabilizer PK083.Materials & methods: Biophysical, cellular and x-ray crystallographic techniques have been employed to elucidate mode action carbazole scaffolds.Results: Targeting an unoccupied subsite heterocycle-substituted PK083 analogs resulted in 70-fold affinity...
Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers this One these molecules, PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with KD = 150 μM, thereby increasing melting temperature protein and slowing its rate aggregation. Incorporation fluorine atoms into small molecule ligands can substantially...
We have previously shown that the thermolabile, cavity-creating p53 cancer mutant Y220C can be reactivated by small-molecule stabilizers. In our ongoing efforts to unearth druggable variants of mutome, we now analyzed effects other cancer-associated mutations at codon 220 on structure, stability, and dynamics DNA-binding domain (DBD). found oncogenic Y220H, Y220N, Y220S are also highly destabilizing, suggesting they largely unfolded under physiological conditions. A high-resolution crystal...
Recently, we have released the de novo design platform REINVENT in version 2.0. This improved and extended iteration supports far more features scoring function components, which allows bespoke tailor-made protocols to maximize impact small molecule drug discovery projects. A major obstacle of generative models is producing active compounds, predictive (QSAR) been applied enrich target activity. However, QSAR are inherently limited by their applicability domains. To overcome these...
The proteins MDM2 and MDM4 are key negative regulators of the tumor suppressor protein p53, which frequently upregulated in cancer cells. They inhibit transactivation activity p53 by binding separately or concert to its domain. is also a ubiquitin ligase that leads degradation p53. Accordingly, important targets for drugs their We found from silico screening confirmed experiment lithocholic acid (LCA) binds sites both with fivefold preference MDM4. LCA an endogenous steroidal bile acid,...
The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of protein that can be targeted by small-molecule stabilizers. Here, we identify different classes small molecules bind to this and determine their binding modes X-ray crystallography. These structures reveal two major conformational states pocket a cryptic, transiently open hydrophobic subpocket is modulated Cys220. In one instance, specifically targeting transient state pyrrole moiety resulted in 40-fold...
A plethora of studies indicate that the development multi-target drugs is beneficial for complex diseases like cancer. Accurate QSAR models each desired targets assist optimization a lead candidate by prediction affinity profiles. Often, drug are sufficiently similar such that, in principle, knowledge can be transferred between to improve model accuracy. In this study, we present two different multi-task algorithms from field transfer learning exploit similarity several target specific models.
Machine learning has been used for estimation of potential energy surfaces to speed up molecular dynamics simulations small systems. We demonstrate that this approach is feasible significantly larger, structurally complex molecules, taking the natural product Archazolid A, a potent inhibitor vacuolar-type ATPase, from myxobacterium Archangium gephyra as an example. Our model estimates energies new conformations by exploiting information previous calculations via Gaussian process regression....
p53 is an important tumor-suppressor protein that mutated in more than 50% of cancers. Strategies for restoring normal function are complicated by the oncogenic properties mutant and have not met with clinical success. To counteract activity, a variety drugs potential to reconvert active wildtype form been developed. However, these associated various negative effects such as cellular toxicity, nonspecific binding other proteins, inability induce response cancer tissue. Here, we report on...
The coronavirus disease 19 (COVID-19) is a rapidly growing pandemic caused by the severe acute respiratory syndrome 2 (SARS-CoV-2). Its papain-like protease (SARS-CoV-2 PLpro) crucial target to halt virus replication. SARS-CoV PLpro and SARS-CoV-2 share an 82.9% sequence identity 100% for binding site reported accommodate small molecules in SARS-CoV. flexible key residues Tyr269 Gln270 small-molecule recognition exist also PLpro. This inspired us use binders generate high-quality DEKOIS 2.0...
The development of orally bioavailable PROTACs presents a significant challenge due to the inflated physicochemical properties such heterobifunctional molecules. Molecules occupying this "beyond rule five" space often demonstrate limited oral bioavailability compounding effects elevated molecular weight and hydrogen bond donor count (among other properties), but it is possible achieve sufficient through optimization. Herein, we disclose design evaluation low (≤1 HBD) fragment screening set...
New derivatives based upon the tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline-piperazinedione scaffolds were synthesized. All compounds evaluated for their ability to inhibit PDE5 in vitro, numerous with IC(50) values low nanomolar range identified including derived from l-tryptophan. Compounds high potency versus then inhibitory activity against other PDEs assess isozyme selectivity. Compound...
Unlocking novel E3 ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on current suite ligands used recruit could limit potential their application. To address this, potent DCAF15 were optimized using cryo-EM supported, structure-based design improve micromolar starting points. A binder, compound 24, was identified and subsequently conjugated into PROTACs against multiple targets. Following attempts degrading a number...
Structure-based virtual screening techniques can help to identify new lead structures and complement other approaches in drug discovery. Prior docking, the data (protein crystal ligands) should be prepared with great attention molecular chemical details.Using a subset of 18 diverse targets from recently introduced DEKOIS 2.0 benchmark set library, we found differences performance two popular docking tools (GOLD Glide) when employing different commercial packages (e.g. MOE Maestro) for...
Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation mutant (mutp53) through restoration wild-type-like function constitutes valuable anticancer therapeutic strategy. order to search for mutp53 reactivators, small library tryptophanol-derived oxazoloisoindolinones was synthesized and the potential compounds reactivators agents investigated in cells xenograft mouse models. By analysis their anti-proliferative effect on...
Bioisosteric replacements are widely used in medicinal chemistry to improve physicochemical and ADME properties of molecules while retaining or improving affinity. Here, using the p53 cancer mutant Y220C as a test case, we investigate both computationally experimentally whether an ethynyl moiety is suitable bioisostere replace iodine ligands that form halogen bonds with protein backbone. This bioisosteric transformation synthetically feasible via Sonogashira cross-coupling. In our case...
The ARID1A and ARID1B subunits are mutually exclusive components of the BAF variant SWI/SNF chromatin remodeling complexes. Loss function mutations in frequently observed various cancers, resulting a dependency on paralog for cancer cell proliferation. However, has never been targeted directly, high degree sequence similarity to poses challenge development selective binders. In this study, we used mRNA display identify peptidic ligands that bind with nanomolar affinities showed selectivity...
Recently, we have reported a systematic comparison of molecular preparation protocols (using MOE or Maestro) in combination with two docking tools (GOLD Glide), employing our DEKOIS 2.0 benchmark sets. Herein, demonstrate how comparable settings data can affect the profile and AUC pROC curves based on variations chemotype enrichment. We show recognition different classes chemotypes performance, particularly early enrichment, monitor changes this behavior score normalization rescoring...