Why it is so difficult to find potent drugs against cancer? - decoding the druggability of molecular targets

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Project Description

The drug discovery process aims at finding novel, more potent small molecules (ligands) that can treat/cure certain human diseases, being a therapeutic agent, or serve in diagnosis of the early stages and progression of the disease. Despite the extensive joint efforts of many laboratories around the world, developing a potent drug is still a major and often a daunting challenge. As of now only 2% of human proteins interact with the currently approved drugs. On the top of that only 10% of human proteins are relevant to the disease. If a drug interacting with the target protein is known, and this interaction leads to therapeutic benefits of patients, then this target protein is called druggable. By simple approximation one can expect that other similar proteins, belonging to the same or related families, can be targeted by ligands - meaning: are druggable. Unfortunately it is often not a case, and only 10-15% of the human genome is predicted to be druggable, with only half of the targets being essential to any disease process.Our group is focused on understanding the molecular determinants driving the protein-protein and protein-ligand interactions, thus druggability of protein targets. We focus our attention on the closely related groups of proteins involved in the gene regulation processes, like histone methyltransferases and demethylases. These proteins covalently modify flexible tails of histones by attaching or removing the -CH3 groups to the side-chains of lysines and arginines. This way they modulate the accessibility of the DNA double strand - genes - toward transcription factor proteins and RNA polymerase. The miss-function of methyltransferases and demethylases is well known to lead to numerous severe cancers in human, like acute leukemia, variety of gastric carcinomas as well as several mental disorders, like schizophrenia.With the combination of molecular biology approaches we prepare and purify the human proteins of interest and subsequently study their structures and interactions with known drugs and other small molecules – ligands - potential candidates for becoming more potent drugs. In the lab we use multidisciplinary approaches and combine several state-of-the-art molecular biology and biophysical techniques. Our main technique, used and developed in the group, is the cutting-edge high-resolution nuclear magnetic resonance (NMR) spectroscopy. The conformational studies in solution are supplemented by other experimental biophysical methods, like X-ray crystallography, isothermal titration calorimetry (ITC), circular dichroism spectroscopy (CD), as well as advanced computational approaches - molecular dynamics (MD) simulations.In conclusion, with the combination of experimental and computational data for selected families of disease related proteins, we try to understand the molecular determinants that make closely related proteins druggable or not druggable.The proposed interdisciplinary project can host two VSRP students.The project offers the wide range of experience, from the protein biochemistry techniques that lead to preparation of biologically relevant material, followed by hands-on experience, i.e. from the design and performing the advanced nuclear magnetic resonance NMR experiments to preparation and running the comprehensive molecular dynamics MD simulations and finally integration of the results coming from the different fields of expertise.Students with the background in bioscience, physics and engineering, who enjoy working in the international and interdisciplinary environments, are welcomed to apply. ​​​
Program - BioScience
Division - Biological and Environmental Sciences and Engineering
Field of Study - ​  bioscience, molecular biology, protein biochemistry, nucleic acids – DNA, computational structural biology, nuclear magnetic resonance NMR, epigenetics  ​

About the
Researcher

Lukasz Jaremko

Assistant Professor, Bioscience

Lukasz Jaremko
​The research of Professor Łukasz Jaremko is focused on atomic-level insight into essential and topical questions of biochemistry and molecular medicine.

Biomolecular nuclear magnetic resonance (NMR) spectroscopy is the key experimental technique used and developed in the lab to tackle challenging macromolecular assemblies. The NMR-based structural studies are often combined with molecular biology and other state-of-the-art biophysical techniques: X-ray crystallography, circular dichroism and molecular dynamics simulations.

The cutting-edge biological NMR spectroscopy gives access to both structure and dynamics, thus providing information on functioning of essential macromolecular systems and their mutual interactions under close-to-native conditions (like aqueous solutions at physiological temperature, lipid membranes, living cell environment). The mutual complementarity between NMR and remaining powerful high-resolution experimental techniques (X-ray crystallography and cryo-electron microscopy) paves the way to more complete description of the pivotal biochemical processes of life and disease.

Desired Project Deliverables

​We offer the students participating in this project to learn: •how to efficiently work in the state-of-the-art protein biochemistry lab, prepare own protein(s) for the biophysical and spectroscopic (e.g. NMR) studies and design the workload; •how to become self-reliant in the design, preparation, running and analysis of the advanced multidimensional NMR experiments, molecular dynamics (MD) simulations of biologically essential macromolecular systems; •how to analyze and integrate the results derived from different computational techniques with the experimentally derived information from the cutting-edge biophysical techniques, including Bio-NMR and X-ray. To complete the above tasks we expect from the students: • a positive approach and strong will to work in the interdisciplinary and international research team; •the preparation of the final report in the article format;•the preparation of presentation that will be given during the group meeting.