Research Lines


InSiliChem is a molecular modeling group with expertise in a wide variety of methods that range from homology modeling, molecular dynamics, protein-ligand dockings or QM based methods. It focuses on two lines: 1) computer based molecular design and 2) interactions of exogenous compounds with living organisms. In both lines, most activities are centered on metal containing systems for which the team has been acquiring expertise over the years. To sustain its investigation, the group also deploys substantial efforts for the development of new software in which GaudiMM is the sparehead.

Phylosophy and Methodology

InSiliChem studies embark a variety of different modeling questions. From sequence analysis, protein-ligand dockings to QM/MM InSiliChem owns expertise that allows to work on very different systems. However, InSiliChem main focuses on systems with little structural information has urge to the development of computational softwares in the last 10 years.

Because of our research interest, we also do methodological development including new software.

Ground Computational Tools

We have a long standing expertise on well established methods in computational chemistry and structural bioinformatics. This includes:
- Homology modeling.
- Molecular Dynamics.
- Protein-ligand dockings and virtual screening.
- Quantum Mechanics and hybrid Quantum Mechanics/Molecular Mechanics.
- Scripting for analysis and modeling.
We adapt our work to the system and can work on standalone or multi-level approaches. This needs in house developments. All our tools can be reached at the InSiliChem GitHub platform.

Multi-level integrative computational strategies

In many of our works, the combination of several techniques is needed and has to be adapted to the problem under investigation. For that reason, we have been working on a multi-level platform named tangram that allow to work under a unique visual interface (UCSF Chimera) with most of the programs that we use (openMM, Gold, GaudiMM, etc.)

GaudiMM and derivatives

A common problem in molecular modeling is the lack of relevant structural starting point. We have been developing during the last 5 years a modeling platform especially dedicated to bring physically sound models using hypothesis driven methodology. Based on a multi-objective genetic algorithm, GaudiMM explores the conformational and chemical space by satisfying molecular descriptors (the objectives) under an evolutive process. GaudiMM is highly modular and particularly helpful for systems where standard methodologies are difficult to apply. It provides first order models that could be refined latter with modeling tools of higher quality.
GaudiMM offers a large ensemble of possibilities and extension. One example is gpathfinder that allows to detect small molecule pathways into proteins.

Predicting metal binding sites

A large part of the activity of the group is dedicated to metal bound systems. In this it is fundamental to have access to predictive tools for the simulation of metal binding process and the determination of metal binding sites in proteins. We have developed several updates in the molecular modeling framework specialized to metal binding processes. Regarding dockings, we have developed extensions into standard docking programs like Gold to deal with metalloligands and also gave such abilities to GaudiMM. We also developed metal binding predictors that allow to identify those regions of the protein that could recognize metal ions or inorganic systems.

Molecular Design

The usefulness of molecular modeling in many fields of chemical sciences is not something to demonstrate. Modeling allows to grasp molecular knowledge that allow chemists, biochemists and nanotechnologists to make stronger hypothesis about the molecular nature of their systems and develop on this. Our group has a large part of its activity dedicated to help in the design of new molecular entities that range from Artificial Metalloenzymes to new Drugs. The particularity of the group is to give priority to metallic systems.

Artificial Metalloenzymes design

Biocatalytic platforms occupy a preferential position in the green chemistry agenda and the catalogue of natural enzymes allied with current biotechnological knowledge offers a unique opportunity in this area. Despite the pleyades of Nature's enzymatic systems, its repertoire only covers a limited scope of the current need of chemical industries of catalytic processes. As a consequence, the discovery of de novo enzymes which activity are absent in Nature is a field of research extremely active.

Amongst the most promising strategies are those based on the insertion of synthetic homogeneous catalyst into a biological scaffold. Somehow reminiscent of naturally occurying hemoenzymes, those systems provide many advantages for the future of biocatalysis. Howevever, the biohybrids designed to date still present many challenges like the identification the exact location of the cofactor, the characterization of catalytically consistent orientations of the substrate or to design variants with specific substrate, regio- or enantiospecificities.

Our group has pioneered researches in the field of artificial metalloenzymes which relied on the development of computational integrative strategies including docking, MD and QM (QM/MM). We also tripled our efforts to update the computational framework with predictive tools for the binding of metallic species to protein scaffold. In particular, we are constantly developing new tools able to predict the binding of metallic compounds to biological hosts using structure based approaches and protein-ligand docking in a first instance.

We are lucky to enjoy collaborations with international leaders in the field like Profs. Thomas Ward (Basel), Gerard Roelfes (Groningen) and Jean-Pierre Mahy (Orsay).

Metallodrug design

Since the emergence of cis-platin as a key player in the fight against cancer, numerous drug design projects have been built around metalloligands. Here, molecular modeling also requires methodologies optimized for the prediction of bio-inorganic adducts. In this field, we already work on a series of metallodrug design problems like the modeling of oxalyplatin interacting with insuline or a series of oxidovanadium(IV) drug candidates.
We apply and test the latests updates in force field approaches in our studies on metallodrugs but, more than antyhing else, we develop metal compatible protein-ligand docking software that give insights to where and how could metal containing species bind to a biological target.
In the recent years, we have been particularly active in showing how computational framework like ours can be vital to predict accurately the binding of metallodrugs to their target when combined with spectroscopic methods. In this, our collaboration with Prof. Eugenio Garribba (University of Sassari, Italy) has been of the most successful.

Supramolecular chemistry

A recent line of research of the group led between professors Maréchal and Ujaque deals with the suported catalysis by supromolecular molecules and more particularly nanocages. Quite orphan from modeling inputs to date, this line of research has a huge potential in which the expertise we gain on catalytic systems and large biomolecular entities are applied with success. Other supramolecular structures we work on are man made Metallopeptides. Those systems have a lot of potential in many medicinal fields and have also shown to be particularly relevant as supramolecular scaffolds. Here again, we combine different level of theory to ascertain the most stable structure of artificial metallopeptides, follow their dynamical behavior and, more recently, predict their binding to key biological partners. We use multi-level approaches and more recently adapted version of GaudiMM on this precise problem. The most representative applicative work on this line is performed in collaboration with Prof. E. Vazquez and M. Vazquez (University of Santiago de Compostela).

Biomedicine and Exogenous compounds

The interaction of exogenous compounds with living organisms is key in many of their functions. It can also be the source of therapies and diseases. The second main line of research of the group focuses on predicting at the molecular level key interactions between exogenous compounds and their target(s).
We center our activities on two categories: metal ions (either beneficial or contaminant) and natural compounds from pharmacophea. In humans we focus on metabolizing enzymes (e.g. cytochromes P450), neurodegenerative disorders and metal related diseases. For non-human organisms, we focus on pathogenic illnesses like malaria, dengue and more recently covid-19.

Metal, contaminants and neurodegenerative diseases

The link between numerous neurodegenerative diseases and metal ions is a question that generate interest in biomedicine. Of the cases more intensively studied is the role of iron, aluminium and copper in the mechanism of aggregation and formation of fibrilar states of b-amyloid systems occuring in alzheimer disease (AD).

Despite years of investigation, it is still not clear what is the molecular pattern that provide metal ions in those systems and reaching experimental information from experimental analysis is still unconclusive. In the last 10 years, we performed a series of studies to ascertain the role of the metal ions in formation of those disease related metallopeptides. Our studies so far allowed to provide with the most reasonable chemical models of the coordination sphere of the metal ions in the amyloid environments especially for copper and aluminium. At the moment, oligomerization processes are under investigation both to better understand the role of the metal in AD but also help to look for therapies based on metal segregation.

Metabolism and small molecules-P450 interactions

Part of the expertise of Dr. Maréchal, the prediction of cytochromes P450 interactions with exogenous compounds and more particular drug compounds is a line of research in expansion at InSiliChem. At the moment, the group applies its expertise to human P450s involved in drug metabolism in humans as well as other members involved in vector bone diseases for the metabolism of insecticides.

Identifying natural product positioning

This final line of search started in 2018 and is concomitent with the previous one. Passionate about natural products impact of health and society, InSiliChem started several projects dedicated to understand at the molecular level the interaction of natural and dietary products (i.e. extract of indigenous medicinal herbs , algae components, molecules of meditarean and other diets) with key targets of human and animal health. Of the projects we could here mention are the prediction of the interaction of dietary products and asian plant extracts with human aromatase, one key enzyme involved in hormone related cancers or the identification of drug candidates from medicinal herbs from the African ecosystem with malaria related enzymes.

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