[Show abstract][Hide abstract] ABSTRACT: Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.
No preview · Article · Nov 2014 · Nature Chemistry
[Show abstract][Hide abstract] ABSTRACT: Helicobacter pylori is associated with inflammatory diseases and can cause gastric cancer and mucosa-associated lymphoma. One of the bacterium's key proteins is high temperature requirement A (HpHtrA) protein, an extracellular serine protease that cleaves E-cadherin of gastric epithelial cells, which leads to loss of cell-cell adhesion. Inhibition of HpHtrA may constitute an intervention strategy against H. pylori infection. Guided by the computational prediction of hypothetical ligand binding sites on the surface of HpHtrA, we performed residue mutation experiments that confirmed the functional relevance of an allosteric region. We virtually screened for potential ligands addressing this surface cleft located between the catalytic and PDZ1 domains. Our receptor-based computational method represents protein surface pockets in terms of graph frameworks and retrieves small molecules that satisfy the constraints given by the pocket framework. A new chemical entity was identified that blocked E-cadherin cleavage in vitro by direct binding to HpHtrA, and efficiently blocked pathogen transmigration across the gastric epithelial barrier. A preliminary crystal structure of HpHtrA confirms the validity of a comparative “homology” model of the enzyme, which we used for the computational study. The results of this study demonstrate that addressing orphan protein surface cavities of target macromolecules can lead to new bioactive ligands.
[Show abstract][Hide abstract] ABSTRACT: Background:
Prioritizing building blocks for combinatorial medicinal chemistry represents an optimization task. We present the application of an artificial ant colony algorithm to combinatorial molecular design (Molecular Ant Algorithm [MAntA]).
In a retrospective evaluation, the ant algorithm performed favorably compared with other stochastic optimization methods. Application of MAntA to peptide design resulted in new octapeptides exhibiting substantial binding to mouse MHC-I (H-2K(b)). In a second study, MAntA generated a new functional factor Xa inhibitor by Ugi-type three-component reaction.
This proof-of-concept study validates artificial ant systems as innovative computational tools for efficient building block prioritization in combinatorial chemistry. Focused activity-enriched compound collections are obtained without the need for exhaustive product enumeration.
Full-text · Article · Mar 2014 · Future medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: Computer algorithms help in the identification and optimization of peptides with desired structure and function. We provide an overview of the current focus of our research group in this field, highlighting innovative methods for peptide representation and de novo peptide generation. Our evolutionary molecular design cycle contains structure-activity relationship modeling by machine-learning methods, virtual peptide generation, activity prediction, peptide syntheses, as well as biophysical and biochemical activity determination. Such interplay between computer-assisted peptide generation and scoring with real laboratory experiments enables rapid feedback throughout the design cycle so that adaptive optimization can take place. Selected practical applications are reviewed including the design of new immunomodulatory MHC-I binding peptides and antimicrobial peptides.
No preview · Article · Dec 2013 · CHIMIA International Journal for Chemistry
[Show abstract][Hide abstract] ABSTRACT: We present the development and application of a new machine-learning approach to exhaustively and reliably identify major histocompatibility complex class I (MHC-I) ligands among all 20(8) octapeptides and in genome-derived proteomes of Mus musculus , influenza A H3N8, and vesicular stomatitis virus (VSV). Focusing on murine H-2K(b), we identified potent octapeptides exhibiting direct MHC-I binding and stabilization on the surface of TAP-deficient RMA-S cells. Computationally identified VSV-derived peptides induced CD8(+) T-cell proliferation after VSV-infection of mice. The study demonstrates that high-level machine-learning models provide a unique access to rationally designed peptides and a promising approach toward "reverse vaccinology".
Full-text · Article · Jun 2013 · ACS Chemical Biology
[Show abstract][Hide abstract] ABSTRACT: Designed peptides that bind to major histocompatibility protein I (MHC-I) allomorphs bear the promise of representing epitopes that stimulate a desired immune response. A rigorous bioinformatical exploration of sequence patterns hidden in peptides that bind to the mouse MHC-I allomorph H-2K(b) is presented. We exemplify and validate these motif findings by systematically dissecting the epitope SIINFEKL and analyzing the resulting fragments for their binding potential to H-2K(b) in a thermal denaturation assay. The results demonstrate that only fragments exclusively retaining the carboxy- or amino-terminus of the reference peptide exhibit significant binding potential, with the N-terminal pentapeptide SIINF as shortest ligand. This study demonstrates that sophisticated machine-learning algorithms excel at extracting fine-grained patterns from peptide sequence data and predicting MHC-I binding peptides, thereby considerably extending existing linear prediction models and providing a fresh view on the computer-based molecular design of future synthetic vaccines. The server for prediction is available at http://modlab-cadd.ethz.ch (SLiDER tool, MHC-I version 2012).
Full-text · Article · Jun 2013 · PLoS Computational Biology
[Show abstract][Hide abstract] ABSTRACT: Modulation of protein-protein interactions (PPI) has emerged as a new concept in rational drug design. Here, we present a computational protocol for identifying potential PPI inhibitors. Relevant regions of interfaces (epitopes) are predicted for three-dimensional protein models and serve as queries for virtual compound screening. We present a computational screening protocol that incorporates two different pharmacophore models. One model is based on the mathematical concept of autocorrelation vectors and the other utilizes fuzzy labeled graphs. In a proof-of-concept study, we were able to identify serine protease inhibitors using a predicted trypsin epitope as query. Our virtual screening framework may be suited for rapid identification of PPI inhibitors and suggesting bioactive tool compounds.
No preview · Article · Feb 2012 · Journal of Computational Chemistry