Cheminformatics | EPFL Graph Search

Cheminformatics (also known as chemoinformatics) refers to the use of physical chemistry theory with computer and information science techniques—so called "in silico" techniques—in application to a range of descriptive and prescriptive problems in the field of chemistry, including in its applications to biology and related molecular fields. Such in silico techniques are used, for example, by pharmaceutical companies and in academic settings to aid and inform the process of drug discovery, for instance in the design of well-defined combinatorial libraries of synthetic compounds, or to assist in structure-based drug design. The methods can also be used in chemical and allied industries, and such fields as environmental science and pharmacology, where chemical processes are involved or studied. History Cheminformatics has been an active field in various guises since the 1970s and earlier, with activity in academic departments and commercial pharmaceutical research and developm

A computational workflow for the expansion of heterologous biosynthetic pathways to natural product derivatives

Jasmin Maria Hafner, Vassily Hatzimanikatis

Plant natural products (PNPs) and their derivatives are important but underexplored sources of pharmaceutical molecules. To access this untapped potential, the reconstitution of heterologous PNP biosynthesis pathways in engineered microbes provides a valuable starting point to explore and produce novel PNP derivatives. Here, we introduce a computational workflow to systematically screen the biochemical vicinity of a biosynthetic pathway for pharmaceutical compounds that could be produced by derivatizing pathway intermediates. We apply our workflow to the biosynthetic pathway of noscapine, a benzylisoquinoline alkaloid (BIA) with a long history of medicinal use. Our workflow identifies pathways and enzyme candidates for the production of (S)-tetrahydropalmatine, a known analgesic and anxiolytic, and three additional derivatives. We then construct pathways for these compounds in yeast, resulting in platforms for de novo biosynthesis of BIA derivatives and demonstrating the value of cheminformatic tools to predict reactions, pathways, and enzymes in synthetic biology and metabolic engineering.

NATURE RESEARCH2021

SPAHM: the spectrum of approximated Hamiltonian matrices representations

Ksenia Briling, Alberto Fabrizio

Physics-inspired molecular representations are the cornerstone of similarity-based learning applied to solve chemical problems. Despite their conceptual and mathematical diversity, this class of descriptors shares a common underlying philosophy: they all rely on the molecular information that determines the form of the electronic Schrödinger equation. Existing representations take the most varied forms, from non-linear functions of atom types and positions to atom densities and potential, up to complex quantum chemical objects directly injected into the ML architecture. In this work, we present the spectrum of approximated Hamiltonian matrices (SPAHM) as an alternative pathway to construct quantum machine learning representations through leveraging the foundation of the electronic Schrödinger equation itself: the electronic Hamiltonian. As the Hamiltonian encodes all quantum chemical information at once, SPAHM representations not only distinguish different molecules and conformations, but also different spin, charge, and electronic states. As a proof of concept, we focus here on efficient SPAHM representations built from the eigenvalues of a hierarchy of well-established and readily-evaluated “guess” Hamiltonians. These SPAHM representations are particularly compact and efficient for kernel evaluation and their complexity is independent of the number of different atom types in the database.

2022

Single-Vesicle Assays Using Liposomes and Cell-Derived Vesicles: From Modeling Complex Membrane Processes to Synthetic Biology and Biomedical Applications

Horst Pick, Ana Catarina Rodrigues Alves, Horst Vogel

The plasma membrane is of central importance for defining the closed volume of cells in contradistinction to the extracellular environment. The plasma membrane not only serves as a boundary, but it also mediates the exchange of physical and chemical information between the cell and its environment in order to maintain intra- and intercellular functions. Artificial lipid- and cell-derived membrane vesicles have been used as closed-volume containers, representing the simplest cell model systems to study transmembrane processes and intracellular biochemistry. Classical examples are studies of membrane translocation processes in plasma membrane vesicles and proteoliposomes mediated by transport proteins and ion channels. Liposomes and native membrane vesicles are widely used as model membranes for investigating the binding and bilayer insertion of proteins, the structure and function of membrane proteins, the intramembrane composition and distribution of lipids and proteins, and the intermembrane interactions during exo- and endocytosis. In addition, natural cell-released microvesicles have gained importance for early detection of diseases and for their use as nanoreactors and minimal protocells. Yet, in most studies, ensembles of vesicles have been employed. More recently, new micro- and nanotechnological tools as well as novel developments in both optical and electron microscopy have allowed the isolation and investigation of individual (sub)micrometer-sized vesicles. Such single-vesicle experiments have revealed large heterogeneities in the structure and function of membrane components of single vesicles, which were hidden in ensemble studies. These results have opened enormous possibilities for bioanalysis and biotechnological applications involving unprecedented miniaturization at the nanometer and attoliter range. This review will cover important developments toward single-vesicle analysis and the central discoveries made in this exciting field of research.

AMER CHEMICAL SOC2018

Single-Vesicle Assays Using Liposomes and Cell-Derived Vesicles: From Modeling Complex Membrane Processes to Synthetic Biology and Biomedical Applications

Horst Pick, Ana Catarina Rodrigues Alves, Horst Vogel

AMER CHEMICAL SOC2018