Organic Chemistry, Medicinal Chemistry and Software Development toward the Development of Cancer Therapeutics

The research in our group spreads over many facets chemistry. Our main aim is to help the discovery and development of new cancer therapeutics, and we attack this global problem from a variety of directions. To this end, we work on diverse projects ranging from organic synthesis to molecular modeling and software development, as we describe below in more detail.

POP/FAP as Potential Targets: Cancer and Alzheimer’s.

This project focuses on computationally-aided design and synthesis of dual inhibitors for cancer research and Alzheimer’s disease. Our targets are two peptidases – prolyl oligopeptidase (POP) and fibroblast activation protein alpha (FAP) – that are linked to angiogenesis, neurodegenerative diseases and tumor growth. We apply Quantum chemical cluster approach (QCCA) and quantum mechanics/molecular mechanics (QM/MM) methods to understand and predict binding kinetics and thermodynamics leading to the design of highly active covalent inhibitors. Using virtual chemistry/biochemistry software, we design molecules that – based on in silico results – would lead to the most efficient path to finding a lead compound.

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Keywords: · QCCA · QM/MM · Computationally-aided Drug Design · Dual inhibition · Organic synthesis · Covalent inhibition

Software Development for Safer Drugs.

The withdrawal of drugs from the market has tremendous negative consequences for patients’ health as well as pharmaceutic companies and is often a result of unforeseen toxicity. These harmful effects may be caused by a drug itself or by compounds formed from its metabolism. An important family of enzymes responsible for the metabolism of xenobiotics in the human body are Cytochromes P450 (CYPs). Thus, prediction of CYP inhibitory potential and/or reactive metabolites formation of a lead compound at an early stage of the drug development process is highly desirable. We study the reactivity of this enzyme using molecular modeling in order to develop software able to predict the how a molecule will be bioactivated by these enzymes or what possible drug-drug interactions may arise during the metabolism.

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Keywords: · Reactive metabolites formation· CYP inhibition · QM/MM · Drug-Drug Interactions · Toxicity

Engineering of cytochrome P450 enzymes for the selective functionalization of pharmaceuticals

Despite decades of research, the regio- and stereoselective hydroxylation of C-H bonds is still a great challenge for organic chemists. Traditional methodologies often require the use of toxic metals at high temperatures, or a series of protection/deprotection steps that negatively impact on the amount of generated waste. Over the last years the use of cytochromes P450 enzymes (CYPs) as biocatalysts for the hydroxylation of C-H bonds has gained momentum. This research consists on utilizing the catalytic power of CYPs through rational protein engineering, within a collaborative effort with other research groups (Dr. Karine Auclair).Computational protocols are employed to predict the effect of certain mutations on substrate binding and catalysis. Then, promising mutants are generated experimentally and tested as biocatalysts for the synthesis of pharmaceutically relevant compounds.
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Keywords: · Protein Engineering· CYPs · Biocatalysts · Green Chemistry · Mutations

New Concept for Force Field Development.

Molecular modeling experiments such as protein-ligand/protein-protein docking and molecular dynamics simulations rely on molecular mechanics schemes, where molecules are considered as assemblies of beads and springs. Fundamentally, the potential energy of these simplified models are obtained by summation of the bonding and non-bonding interactions encoded as a set of functions and parameters, referred to as a force field. These parameters are traditionally derived from a large training set of small molecules/fragments and organized by atom types. We work on alternative approaches to develop new force fields based on chemistry knowledge rather than training. Specific parameters are derived on-the-fly from atomic properties and are expected to be more accurate that generic atom type-based parameters.

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Keywords: · Molecular Mechanics · Force Fields · Hyperconjugation · Qunatification of Chemistry Principles

Synthesis and Catalysis for Easier Drug Production.

Carbohydrate Chemistry.

Currently, preparation of synthetic polysaccharides on large scale is not cost-efficient hampering their availability. Synthetic strategies towards oligosaccharides are primarily based upon numerous time-consuming, costly and non-environmentally friendly protection/deprotection steps. We propose to develop a novel synthetic strategy to prepare polysaccharides in a concise, scalable and green approach. We first designed directing-protecting groups (DPGs) which, when attached to glucopyranosides, controlled the regioselectivity of a variety of chemical reactions (e.g., acylation, alkylation and glycosylation). For example, when glycosylating sugars featuring a DPG, such as 6-O protected glucosides, a single disaccharide over six possible isomers was obtained, significantly improving the regio- and stereoselectivity of this reaction. We then developed temporary directing-protecting groups (TDPGs) based on labile functional groups (i.e. boronic esters) which form weak covalent bonding with the sugar unit, in a one-pot process. Using this new strategy, we were able to monoacylate an unprotected methylglucoside (referred as a tetraol) with tunable regioselectivity on either OH-2 or OH-3 in a single step. We are currently applying our newly developed method to stereo- and regioselective glycosylation.

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Keywords: · Carbohydrate Chemistry · Regioselectivity · Protecting groups · Green chemistry · Medicinal chemistry

Asymmetric Synthesis and Development of ACE. The long term goal of this research is the delivery of a suite of programs or protocols that will have been experimentally validated for catalyst discovery and the delivery of efficient catalysts in a time and cost efficient manner.

Catalyst discovery and computers. The catalyst discovery process as practised now is time consuming , expensive, and often serendipitous . Computational prediction would enable the chemists to reduce the cost and accelerate the lead generation and optimization steps . Until recently, conventionally available computer power has been insufficient to tackle the combinatorial problem of molecular design through virtual screening. This computational power is now available and the time is ripe for the development of more predictive methods. Indeed, the use of computer-aided molecular design methods in the field of drug development is well established but focused almost exclusively on ground state structures. Meanwhile, few groups have focused on the development of rapid and predictive tools for de novo design of asymmetric organic reactions which require the more challenging and complex study of flexible transition state (TS) structures. Apart from the highly computer time-intensive density functional theory (DFT), ab initio and semi-empirical methods, which are restricted to small systems, little attention has been directed to TS structure analysis by fast and accurate in silico screening methods. In particular, few predictive molecular mechanics-based models have been designed to address TS structures. To this end, we have recently reported a simple yet accurate strategy for describing transition states using molecular mechanics (MM) methods and a genetic algorithm to account for flexibility of the TS structures and implemented it into an independent program ACE. Development of a fully automated computational method for rapid virtual screening of potential asymmetric catalysts has followed and recently entered the validation stage.

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Synthesis of medium-sized rings as potential catalysts.As for the medicinal chemistry projects above, molecular discovery often requires that some synthetic methodologies are developed. In this context, we have developed an expedient method to prepare chiral oxazepanes. With this method in hand, we are currently developing catalysts using a combination of synthesis and ACE-guided design.

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