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Chemical Space Design of Small Molecules and Peptides

English title Chemical Space Design of Small Molecules and Peptides
Applicant Reymond Jean-Louis
Number 178998
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie, Biochemie und Pharmazie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.04.2018 - 31.03.2022
Approved amount 1'489'994.00
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Keywords (7)

small molecule drugs; cheminformatics; chemical space; drug design; dendrimers; antimicrobial agents; peptides

Lay Summary (French)

Lead
L'espace chimique des molécules organiques et des peptides
Lay summary
Le progrès de la médecine moderne dépent en grande partie de la découverte de nouveaux médicaments. Dans ce projet nous abordons la conception de nouvelle classes de molécules thérapeutiques qui puissent surmonter les difficultés rencontrées avec la plupart des médicaments, qui sont le manque de sélectivité et la formation de métabolites. Nous abordons ce problème par le biais du concept de l'espace chimique, qui permet de décrire les propriétés moléculaires sous forme de coordonnées spatiales. Nous dévelopons des méthodes de calcul pour énumérer et explorer des bases de données de molécules de type "big data", par lesquelles nous choississons des molécules que nous synthétisons et testons ensuite au laboratoire. Nous nous intéressons particulièrement aux petites molécules organiques ainsi qu'aux peptides dendritiques et polycycliques. 
Direct link to Lay Summary Last update: 26.04.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Classifying natural products from plants, fungi or bacteria using the COCONUT database and machine learning
Capecchi Alice, Reymond Jean-Louis (2021), Classifying natural products from plants, fungi or bacteria using the COCONUT database and machine learning, in Journal of Cheminformatics, 13(1), 82-82.
An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate
Erzina Dina, Capecchi Alice, Javor Sacha, Reymond Jean‐Louis (2021), An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate, in Angewandte Chemie International Edition, 60(50), 26403-26408.
A mixed chirality α-helix in a stapled bicyclic and a linear antimicrobial peptide revealed by X-ray crystallography
Baeriswyl Stéphane, Personne Hippolyte, Di Bonaventura Ivan, Köhler Thilo, van Delden Christian, Stocker Achim, Javor Sacha, Reymond Jean-Louis (2021), A mixed chirality α-helix in a stapled bicyclic and a linear antimicrobial peptide revealed by X-ray crystallography, in RSC Chemical Biology, 2(6), 1608-1617.
Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB‐17 Fragment Library
Pujol‐Giménez Jonai, Poirier Marion, Bühlmann Sven, Schuppisser Céline, Bhardwaj Rajesh, Awale Mahendra, Visini Ricardo, Javor Sacha, Hediger Matthias A., Reymond Jean‐Louis (2021), Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB‐17 Fragment Library, in ChemMedChem, 16(21), 3306-3314.
Machine learning designs non-hemolytic antimicrobial peptides
Capecchi Alice, Cai Xingguang, Personne Hippolyte, Köhler Thilo, van Delden Christian, Reymond Jean-Louis (2021), Machine learning designs non-hemolytic antimicrobial peptides, in Chemical Science, 12(26), 9221-9232.
Peptide Dendrimers: From Enzyme Models to Antimicrobials and Transfection Reagents
Reymond Jean-Louis (2021), Peptide Dendrimers: From Enzyme Models to Antimicrobials and Transfection Reagents, in CHIMIA, 75(6), 535-535.
The antibacterial activity of peptide dendrimers and polymyxin B increases sharply above pH 7.4
Cai Xingguang, Javor Sacha, Gan Bee Ha, Köhler Thilo, Reymond Jean-Louis (2021), The antibacterial activity of peptide dendrimers and polymyxin B increases sharply above pH 7.4, in Chemical Communications, 57(46), 5654-5657.
Prediction of chemical reaction yields using deep learning
Schwaller Philippe, Vaucher Alain C, Laino Teodoro, Reymond Jean-Louis (2021), Prediction of chemical reaction yields using deep learning, in Machine Learning: Science and Technology, 2(1), 015016-015016.
Retrosynthetic accessibility score (RAscore) – rapid machine learned synthesizability classification from AI driven retrosynthetic planning
Thakkar Amol, Chadimová Veronika, Bjerrum Esben Jannik, Engkvist Ola, Reymond Jean-Louis (2021), Retrosynthetic accessibility score (RAscore) – rapid machine learned synthesizability classification from AI driven retrosynthetic planning, in Chemical Science, 12(9), 3339-3349.
Peptides in chemical space
Capecchi Alice, Reymond Jean-Louis (2021), Peptides in chemical space, in Medicine in Drug Discovery, 9, 100081-100081.
Stereorandomization as a Method to Probe Peptide Bioactivity
Siriwardena Thissa N., Gan Bee-Ha, Köhler Thilo, van Delden Christian, Javor Sacha, Reymond Jean-Louis (2021), Stereorandomization as a Method to Probe Peptide Bioactivity, in ACS Central Science, 7(1), 126-134.
A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D‐Shaped Triquinazine Ring System from Chemical Space
Meier Kris, Arús‐Pous Josep, Reymond Jean‐Louis (2021), A Potent and Selective Janus Kinase Inhibitor with a Chiral 3D‐Shaped Triquinazine Ring System from Chemical Space, in Angewandte Chemie International Edition, 60(4), 2074-2077.
Synergistic Effect of Propidium Iodide and Small Molecule Antibiotics with the Antimicrobial Peptide Dendrimer G3KL against Gram-Negative Bacteria
Gan Bee-Ha, Cai Xingguang, Javor Sacha, Köhler Thilo, Reymond Jean-Louis (2020), Synergistic Effect of Propidium Iodide and Small Molecule Antibiotics with the Antimicrobial Peptide Dendrimer G3KL against Gram-Negative Bacteria, in Molecules, 25(23), 5643-5643.
One molecular fingerprint to rule them all: drugs, biomolecules, and the metabolome
Capecchi Alice, Probst Daniel, Reymond Jean-Louis (2020), One molecular fingerprint to rule them all: drugs, biomolecules, and the metabolome, in Journal of Cheminformatics, 12(1), 43-43.
Assigning the Origin of Microbial Natural Products by Chemical Space Map and Machine Learning
Capecchi Alice, Reymond Jean-Louis (2020), Assigning the Origin of Microbial Natural Products by Chemical Space Map and Machine Learning, in Biomolecules, 10(10), 1385-1385.
Transfecting tissue models with CRISPR/Cas9 plasmid DNA using peptide dendrimers
Zamolo Susanna J., Darbre Tamis, Reymond Jean-Louis (2020), Transfecting tissue models with CRISPR/Cas9 plasmid DNA using peptide dendrimers, in Chemical Communications, 56(80), 11981-11984.
Fluorescent Peptide Dendrimers for siRNA Transfection: Tracking pH Responsive Aggregation, siRNA Binding, and Cell Penetration
Heitz Marc, Zamolo Susanna, Javor Sacha, Reymond Jean-Louis (2020), Fluorescent Peptide Dendrimers for siRNA Transfection: Tracking pH Responsive Aggregation, siRNA Binding, and Cell Penetration, in Bioconjugate Chemistry, 31(6), 1671-1684.
The Generated Databases (GDBs) as a Source of 3D-shaped Building Blocks for Use in Medicinal Chemistry and Drug Discovery
Meier Kris, Bühlmann Sven, Arús-Pous Josep, Reymond Jean-Louis (2020), The Generated Databases (GDBs) as a Source of 3D-shaped Building Blocks for Use in Medicinal Chemistry and Drug Discovery, in CHIMIA, 74(4), 241-241.
ChEMBL-Likeness Score and Database GDBChEMBL
Bühlmann Sven, Reymond Jean-Louis (2020), ChEMBL-Likeness Score and Database GDBChEMBL, in Frontiers in Chemistry, 8, 46.
Populating Chemical Space with Peptides Using a Genetic Algorithm
Capecchi Alice, Zhang Alain, Reymond Jean-Louis (2020), Populating Chemical Space with Peptides Using a Genetic Algorithm, in Journal of Chemical Information and Modeling, 60(1), 121-132.
Fluorescence Imaging of Bacterial Killing by Antimicrobial Peptide Dendrimer G3KL
Gan Bee-Ha, Siriwardena Thissa N., Javor Sacha, Darbre Tamis, Reymond Jean-Louis (2019), Fluorescence Imaging of Bacterial Killing by Antimicrobial Peptide Dendrimer G3KL, in ACS Infectious Diseases, 5(12), 2164-2173.
Systems Chemical BiologyMethods and Protocols
Awale Mahendra, Reymond Jean-Louis (2019), Systems Chemical BiologyMethods and Protocols, Springer New York, New York, NY.
X‐Ray Crystal Structure of a Second‐Generation Peptide Dendrimer in Complex with Pseudomonas aeruginosa Lectin LecB
Baeriswyl Stéphane, Javor Sacha, Stocker Achim, Darbre Tamis, Reymond Jean‐Louis (2019), X‐Ray Crystal Structure of a Second‐Generation Peptide Dendrimer in Complex with Pseudomonas aeruginosa Lectin LecB, in Helvetica Chimica Acta, 102(9), e1900178.
Stereoselective pH Responsive Peptide Dendrimers for siRNA Transfection
Heitz Marc, Javor Sacha, Darbre Tamis, Reymond Jean-Louis (2019), Stereoselective pH Responsive Peptide Dendrimers for siRNA Transfection, in Bioconjugate Chemistry, 30(8), 2165-2182.
PubChem and ChEMBL beyond Lipinski
Capecchi Alice, Awale Mahendra, Probst Daniel, Reymond Jean‐Louis (2019), PubChem and ChEMBL beyond Lipinski, in Molecular Informatics, 38(5), 1900016-1900016.
X-ray Crystal Structures of Short Antimicrobial Peptides as Pseudomonas aeruginosa Lectin B Complexes
Baeriswyl Stéphane, Gan Bee-Ha, Siriwardena Thissa N., Visini Ricardo, Robadey Maurane, Javor Sacha, Stocker Achim, Darbre Tamis, Reymond Jean-Louis (2019), X-ray Crystal Structures of Short Antimicrobial Peptides as Pseudomonas aeruginosa Lectin B Complexes, in ACS Chemical Biology, 14(4), 758-766.
Antimicrobial Peptide Dendrimer Chimera
Siriwardena Thissa N., Lüscher Alexandre, Köhler Thilo, van Delden Christian, Javor Sacha, Reymond Jean‐Louis (2019), Antimicrobial Peptide Dendrimer Chimera, in Helvetica Chimica Acta, 102(4), e1900034-e1900034.
Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning
Awale Mahendra, Reymond Jean-Louis (2019), Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning, in Journal of Chemical Information and Modeling, 59(1), 10-17.
Optimizing Antimicrobial Peptide Dendrimers in Chemical Space
Siriwardena Thissa N., Capecchi Alice, Gan Bee‐Ha, Jin Xian, He Runze, Wei Dengwen, Ma Lan, Köhler Thilo, van Delden Christian, Javor Sacha, Reymond Jean‐Louis (2018), Optimizing Antimicrobial Peptide Dendrimers in Chemical Space, in Angewandte Chemie International Edition, 57(28), 8483-8487.
An antimicrobial bicyclic peptide from chemical space against multidrug resistant Gram-negative bacteria
Di Bonaventura Ivan, Baeriswyl Stéphane, Capecchi Alice, Gan Bee-Ha, Jin Xian, Siriwardena Thissa N., He Runze, Köhler Thilo, Pompilio Arianna, Di Bonaventura Giovanni, van Delden Christian, Javor Sacha, Reymond Jean-Louis (2018), An antimicrobial bicyclic peptide from chemical space against multidrug resistant Gram-negative bacteria, in Chemical Communications, 54(40), 5130-5133.

Collaboration

Group / person Country
Types of collaboration
Prof. Christian Van Delden, Université de Genève Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
DMCCB Basel Symposium 2022: «Intrinsically Disordered Proteins as Drug Targets» Talk given at a conference Exploring bicyclic diamines as drug scaffolds 31.01.2022 Basel, Switzerland Carrel Aline;
3rd Alpine Winter Conference on Medicinal and Synthetic Chemistry Poster Exploring bicyclic diamines as drug scaffolds 30.01.2022 Virtual Event, Austria Carrel Aline;
ETH Zürich, Laboratorium für Organische Chemie Individual talk Chemical Space Inspired Design of Small Molecules and Peptides 15.11.2021 Zürich, Switzerland Reymond Jean-Louis;
Genentech Individual talk New Chemical Space and How to Get There: Insights from Peptide Dendrimers and Deep Learning for Reaction Prediction 14.09.2021 online, United States of America Reymond Jean-Louis;
SCS Fall meeting 2021 Poster Design of new anticancer peptides using PDGA 10.09.2021 Virtual event, Switzerland Zakharova Elena;
SCS Fall Meeting 2021 Poster Synthesis of new building blocks from the chemical universe database GDB 10.09.2021 Virtual Event, Switzerland Carrel Aline;
EFMC International Symposium on Medicinal Chemistry Talk given at a conference Synthesis of new building blocks from the chemical universe database GDB 29.08.2021 Virtual Event, Switzerland Carrel Aline;
ACS National Meeting in Atlanta Talk given at a conference Targeted Expansion of the Peptide Chemical Space by Enumeration, Genetic Algorithms, and Machine Learning 24.08.2021 online, United States of America Reymond Jean-Louis;
Peptide Therapeutics Forum Talk given at a conference Antimicrobial Peptides from Chemical Space and Beyond 20.08.2021 Basel, Switzerland Reymond Jean-Louis;
RICT 2021, 56th International Conference On Medicinal Chemistry Poster Synthesis of new building blocks from the chemical universe database GDB 07.07.2021 Virtual Event, Switzerland Carrel Aline;
HES-SO Valais Individual talk Antimicrobial Peptides and Dendrimers 30.03.2021 Sion, Switzerland Reymond Jean-Louis;
Frontiers in Medicinal Chemistry 2021 Poster Synthesis of new building blocks from the chemical universe database GDB 07.03.2021 Virtual Event, Switzerland Carrel Aline;
Reaxys R&D Network Mini Symposium Talk given at a conference The GDB Project 25.02.2021 online, Switzerland Reymond Jean-Louis;
NIH Virtual Workshop on Ultra-Large Chemistry Databases Talk given at a conference The GDB databases and their use for drug discovery 02.12.2020 online, United States of America Reymond Jean-Louis;
University of Leeds, UK Individual talk Chemical Space Approaches for Small Molecule Drugs and Peptides 26.11.2020 online, Great Britain and Northern Ireland Reymond Jean-Louis;
Seminar at Syngenta Individual talk Chemical Space Guided Discovery of Small Molecules and Peptides 13.11.2020 n/n, Switzerland Reymond Jean-Louis;
RSC Desktop Seminar Individual talk GDB and the Chemical Space 07.10.2020 online, Great Britain and Northern Ireland Reymond Jean-Louis;
EFMC-YMCS 2020 Talk given at a conference Advanced Building Blocks from The Chemical Universe Database GDB and Their Use to Create Potent Janus Kinase Inhibitors 10.09.2020 Online, Switzerland Meier Kris;
First Year Graduate Student Symposium 2020 Talk given at a conference Synthesis of new building blocks for medicinal chemistry 07.09.2020 Bern, Switzerland Carrel Aline;
SCS Fall meeting 2020 Poster Peptide dendrimers for cisplatin delivery to cancer cells 25.08.2020 Virtual event, Switzerland Zakharova Elena;
SCS Fall Meeting 2020 Poster X-Ray Crystallographic Studies of Short Antimicrobial Helical Peptides against Multidrug Resistant Gram-Negative Bacteria 25.08.2020 Bern (online), Switzerland Bühlmann Sven;
Peptide Therapeutics Forum Talk given at a conference The Peptide Chemical Space as Tool for Discovery and Optimization 17.08.2020 Basel, Switzerland Reymond Jean-Louis;
NUI Galway, School of Chemistry Individual talk GDB and the Chemical Space 10.07.2020 Galway, Ireland Reymond Jean-Louis;
Department of Chemistry, EPFL Lausanne Individual talk GDB and the Chemical Space 15.06.2020 Lausanne, Switzerland Reymond Jean-Louis;
RISE AI Workshop Talk given at a conference GDB and the Chemical Space 29.05.2020 Online, Switzerland Reymond Jean-Louis;
Small Molecule Day Talk given at a conference GDB and the Chemical Space 24.03.2020 Oxford, Great Britain and Northern Ireland Reymond Jean-Louis;
2nd Anglo-Swiss Symposium 2020 Poster Peptide Dendrimer Analogues of the Multiple Sclerosis Drug Glatiramer Acetate 04.02.2020 Basel, Switzerland Erzina Dina;
Chemical Biology International Symposium 2020 Poster Glatiramer-like Peptide Dendrimers for Multiple Sclerosis treatment 22.01.2020 Genf, Switzerland Erzina Dina;
20 years Lipinski RSC Symposium Talk given at a conference Chemical Space Adventures Below and Beyond Lipinski 20.11.2019 Nottingham, Great Britain and Northern Ireland Reymond Jean-Louis;
Novartis Day Poster Synthetic Accessibility and Natural Product Likeness of GDB Molecules 14.11.2019 Basel, Switzerland Bühlmann Sven;
Seminar at Roche Individual talk Big Data in Chemistry – Cheminformatics 11.11.2019 Basel, Switzerland Reymond Jean-Louis;
4th SCS-Syngenta Symposium 2019 Poster Not known 17.10.2019 Stein, Switzerland Meier Kris;
Antibiotics Forum Basel Talk given at a conference Fighting Multidrug Resistant Bacteria with Peptide Dendrimers and Bicyclic Peptides 10.09.2019 Basel, Switzerland Reymond Jean-Louis;
20th SCI/RSC Medicinal Chemistry Symposium 2nd Anglo-Swiss Symposium Poster Using chemical biology to identify new targets for Medicinal Chemistry 08.09.2019 Cambridge, Great Britain and Northern Ireland Meier Kris;
SCS Fall Meeting 2019 Poster X-ray structure of a second generation peptide dendrimer as Lectin complex at 1.4 Å resolution 06.09.2019 Zürich, Switzerland Baeriswyl Stéphane;
SCS Fall Meeting 2019 Poster Synthetic Accessibility and Natural Product Likeness of GDB Molecules 06.09.2019 Zürich, Switzerland Bühlmann Sven;
SCS Fall Meeting 2019 Talk given at a conference Advanced building blocks for medicinal chemistry from the chemical universe database GDB 06.09.2019 Zürich, Switzerland Meier Kris;
Public outreach at the Digitalisierungstag Bern Talk given at a conference Wirkstoffe in Virtual Reality 03.09.2019 Bern, Switzerland Reymond Jean-Louis;
Lecture at Israel chemical society meeting Talk given at a conference Peptide dendrimers and bicyclic peptides as antimicrobial agents 19.06.2019 Rehovot, Israel Reymond Jean-Louis;
Seminar at ETH Zürich Individual talk Fighting Multidrug Resistant Bacteria with Peptide Dendrimers and Bicyclic Peptides 13.06.2019 Zürich, Switzerland Reymond Jean-Louis;
C4 Workshop Individual talk Chemical space for small molecules and beyond 05.06.2019 Zürich, Switzerland Reymond Jean-Louis;
TOKS conference Talk given at a conference Fighting Multidrug Resistant Bacteria with Peptide Dendrimers and Bicyclic Peptides 03.05.2019 Kopenhagen, Denmark Reymond Jean-Louis;
Seminar at Xiamen University Individual talk Antimicrobial Peptide Dendrimers and Bicyclic Peptides from Chemical Space 25.04.2019 Xiamen, China Reymond Jean-Louis;
Seminar at the Cancer Research Center Individual talk Chemical space guided medicinal chemistry 17.04.2019 Auckland, New Zealand Reymond Jean-Louis;
RSC symposium Talk given at a conference Fighting Multidrug Resistant Bacteria with Peptide Dendrimers and Bicyclic Peptides 10.04.2019 Melbourne, Australia Reymond Jean-Louis;
ACS National Meeting, CINF41 Talk given at a conference Exploring chemical space at http://gdb.unibe.ch 01.04.2019 Orlando, United States of America Reymond Jean-Louis;
Seminar at Novartis Individual talk Chemical space for small molecules and beyond 21.03.2019 Basel, Switzerland Reymond Jean-Louis;
Streamlining Drug Discovery Talk given at a conference Enumerating and visualizing chemical space 14.02.2019 Frankfurt, Germany Reymond Jean-Louis;
Lecture at Basler Chemische Gesellschaft, University of Basel Individual talk Chemical space for drug discovery 31.01.2019 Basel, Switzerland Reymond Jean-Louis;
SCS Fall Meeting 2018 Poster Crystallographic study of an antimicrobial bicyclic peptide from chemical space 07.09.2018 Lausanne, Switzerland Baeriswyl Stéphane;
SCS Fall Meeting 2018 Poster Not known 07.09.2018 Lausanne, Switzerland Meier Kris;
Villars Summer School in Chemical Biology Poster Crystallographic study of an antimicrobial bicyclic peptide from chemical space 19.08.2018 Villars-sur-Ollon, Switzerland Baeriswyl Stéphane;
Seminar at TU Dortmund Individual talk Chemical Space as a tool for drug discovery: from fragments to peptides 04.07.2018 Dortmund, Germany Reymond Jean-Louis;
6th International Symposium on Biomedical Applications of Dendrimers - Biodendrimer 2018 Poster Discovery of Novel Antimicrobial Peptide Dendrimer from Chemical Space 04.06.2018 Urbino, Italy Siriwardena Thissa Nuwan;
Seminar at Biozentrum Individual talk Chemical space guided discovery of antimicrobial peptides 30.04.2018 Basel, Switzerland Reymond Jean-Louis;
Seminar at Astra Zeneca Individual talk The Chemical Universe Database: Molecules, Fragments and Ring Systems 24.04.2018 Möldnal, Sweden Reymond Jean-Louis;


Associated projects

Number Title Start Funding scheme
125762 NCCR TransCure: From transport physiology to identification of therapeutic targets (phase I) 01.11.2010 National Centres of Competence in Research (NCCRs)
167048 Antimicrobial peptide dendrimers (AMPD) and bicyclic peptides (AMBP) as therapeutic agents against multidrug resistant bacteria 01.03.2017 NRP 72 Antimicrobial Resistance
165997 Exploiting and Extending GDB for Drug Discovery 01.05.2016 Project funding (Div. I-III)
159941 A Chemical Space Approach to Bioactive Peptides 01.04.2015 Project funding (Div. I-III)
155982 Controlling multi-antibiotic resistant bacteria with antimicrobial peptide dendrimers (AMPD) 01.10.2015 China
196862 Structural and mechanistic investigations of membrane-integral enzymes involved in eukaryotic protein N-glycosylation pathway 01.01.2021 Project funding (Div. I-III)
205330 A nitrogen cooled NMR cryoprobe and a new console for the measurement of low concentrated samples 01.01.2022 R'EQUIP
207976 Chemical Space Inspired Building Blocks and Peptides for Medicinal Chemistry 01.04.2022 Project funding (Div. I-III)

Abstract

The continuous discovery of new drugs is essential to the success of modern medicine. Here we address the question of designing new structural families of small molecule drugs and peptides to help overcome limitations encountered with currently used compound types such as lack of selectivity and metabolic instability. We guide our molecular designs by exploiting the concept of chemical space, which relates molecular properties to spatial coordinates. We aim to develop computational tools for enumerating and exploring large compound databases, and to synthesize, test and investigate compounds selected using these tools with focus on new small molecule building blocks, peptide dendrimers and polycyclic peptides.
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