MEDCHEM.fi
Institute of Biomedicine
University of Turku
About Us
We are an academic research group at the University of Turku, Finland. We aim to develop novel methods for computational drug discovery and utilize those methods in drug discovery, thus, Tiny Molecules and Big Discoveries.
What could be better than sitting by your computer all day and changing the world!
We focus on developing novel tools for efficient virtual screening and discovering small-molecule and macrocyclic ligands for selected target proteins. Our special interest is in the identification of first-in-class protein-protein interaction modulators. What does that mean, you ask? Scroll down to find out!
If you already scrolled down and still have no idea what we do here, look at our publications. If you are interested in what we are doing right now, look at our ongoing projects here! You can also find more details about our research topics here.
News
24/9/2024
Aliaa’s first-author paper published! Congrats! Now, there is content for her Ph.D. thesis page titled “List of Original Publications.” Hopefully, we will see the next one very soon.
“Atomistic simulations reveal impacts of missense mutations on the structure and function of SynGAP1" is published in Briefings in Bioinformatics (IF=6.8; JUFO=2) and is an open-access paper, available at the journal site:
https://academic.oup.com/bib/article/25/6/bbae458/7765456
Team: Aliaa, Olli and Pekka from medchem.fi, and Li-Li Li and Michael Courtney from Turku Bioscience.
6/9/2024
Our Dynamic Duo for the summer has flown the nest—best of luck with those Master’s studies (we do not want to say goodbye, just “see you soon!”).
Their time here was a blast, filled with creative sparks and impressive research wins. Plus, thanks to them, our web pages got a makeover, and even Coolio became an Instagram sensation!
Now, if only publishing papers were as easy as becoming IG famous... Let's get to it!
12/8/2024
Paola’s 1st paper for her PhD was published! Congrats!
“Building shape-focused pharmacophore models for effective docking screening,” has been published online in the Journal of Cheminformatics! 🎉 You can read it here:
https://jcheminf.biomedcentral.com/articles/10.1186/s13321-024-00857-6
This study introduces a new computer-aided drug discovery method tested with molecular docking rescoring in mind. By focusing on shape similarity, we’ve developed a new pharmacophore modeling method that shows great promise.
Team: Paola, Olli and Pekka from UTU, and Jukka V Lehtonen from ÅAU.
People
Principal investigators
Olli Pentikäinen PhD, Head of MedChem.fi
Professor of Medicinal Chemistry (Institute of Biomedicine, UTu)
Associate Professor (Docent) in Biochemistry (Department of Biochemistry, UTu)
CEO of Aurlide Ltd.
Business Development
Tero Linnanen PhD
Senior Business Champion
Kseniia Petrova-Szczasiuk MSc
Business Champion
Senior Scientists
Mira Ahinko PhD
Senior Scientist
Research interests: Software development
Shelly Pathania PhD
Senior Scientist
Research interests: Medicinal Chemistry
Santeri Puranen PhD
Consulting Scientist
Research interests: Software Development
Post-graduate students
Aliaa Ali MSc
Molecular Dynamics
Paola Moyano-Gómez MSc
Molecular Discovery, Virtual Screening
Sakari Lätti MSc
Software Development
Sara Soikkeli MSc
Machine Learning and Software Development
Summer 2024 Alumni
Henna-Riikka Otranen BSc
Structural Bioinformatics
Veera Soininen BSc
Computer-aided drug discovery, webpage design
Summer 2023 Alumni
Henna-Riikka Otranen BSc
Structural Bioinformatics
Photo by Elisa Postila
@elisapostila
Funding
Business Finland 700kE 2024-2025
“Business Finland granted Professor Olli Pentikäinen and Docent Ulla Pentikäinen's research groups funding of 0.7 million euros for cancer drug development. The funding will accelerate the development of treatments for various types of cancer for which no treatment methods are yet known.”
Business Finland offers funding for research, product development, and many kinds of business development needs, especially for small and medium-sized companies. Large companies and research organizations can receive funding for joint projects with smaller companies.
Novo Nordisk Foundation 6MDKK 2022-2025
“We received a grant for developing a computer platform that can identify protein-protein interactions. Understanding these interactions is important to develop drugs against diseases that cannot currently be treated, such as several types of cancer or many diseases of the nervous system. Together with our colleagues, we are at the forefront of understanding how protein-protein interactions can become targets for drugs. Our approach may potentially revolutionize the entire field of developing novel drugs for diseases that are currently hard to combat.”
Novo Nordisk Foundation is an independent, Danish enterprise foundation that supports scientific, humanitarian, and social causes. They support a wide range of projects and initiatives that help to promote human health and the sustainability of the planet.
SynGAP Research Fund $100k 2023-2024
“The SynGAP Research Fund 501(c)(3) announced a $100,000 grant to researchers Pekka Postila and Olli Pentikäinen from the Institute of Biomedicine and InFLAMES Flagship at the University of Turku.” Read more here.
SynGAP Research Fund (SRF) is a global group of families committed to accelerating the science to cure SYNGAP1 & to supporting each other.
Research and Publications
Below, you will hear a little about our research.
You can read more from our publications.
Software
The one and only Panther for NIB-screening
You know Elvis is not dead but sits back in his rocking chair, a.k.a. Rocker for AUCs etc
Keep your multiconformation data - and do many other things - with SDFCONF.
Use the (brute) Force... to Optimize your Panther-models (or similar)
Utility tool(s) for protein-ligand modeling
Protein-Protein Interaction Modulators
One of our special interests is the rational discovery of protein-protein interaction (ppi) modulators. Indeed, it is considered to be, if not impossible, highly challenging. There are very few reported successes, where the first-in-class small molecule ppi modulators would had been identified via virtual screening, from which we were the very first ones - and now we have further successes, seven in total and increasing. Note that we have not only succeeded with blockers but also with identification of binding enhancers.
Our protein-protein interaction modulator discovery begun with collagen-binding integrins. The project started from protein modeling, went to ligand identification, optimization, and tool compound production. This was one of the key factors in our learning curve towards rationalization of the process (trial and error).
Macrocycle Discovery and Synthesis
Rational discovery of drug like or slightly beyond the Ro5 ligands to modulate selected drug discovery targets
How about finding a new type of ligands to treat diseases? Although we work a lot with the discovery of small molecules, the traditional small molecules are often too small or unspecific to become approved drugs, and the development and production of biologicals are too expensive. Then, the solution could be macrocycles. We develop macrocycles consisting of 3-5 amino acids cyclized with various strategies. Our discovery is guided by the target protein structures (and models of them) with an accurate prediction of pharmacokinetic properties - especially the cellular permeability.
We develop novel methods for the rational macrocycle discovery, and utilize these methods to identify novel type of function modulators for various drug discovery targets.
You can find more information from our current research projects (WEE1, KRAS, TNFa, EGFR, etc.).
Here is a look at our ONGOING PROJECTS.
Identifying Novel WEE1 Inhibitors
A wee1 bit of information: Project Introduction
The WEE1 kinase is a critical cell cycle regulator, playing a pivotal role in the G2 checkpoint to prevent cells with DNA damage from entering mitosis. Targeting WEE1 has emerged as a promising strategy in cancer therapy, as its inhibition can enhance the efficacy of DNA-damaging agents and induce synthetic lethality in tumors with specific genetic backgrounds. This project, which is at the forefront of innovation, seeks to identify and characterize novel WEE1 inhibitors that can be developed into potent therapeutic agents. Through high-throughput screening, computational modeling, and biochemical assays, we aim to discover compounds that effectively inhibit WEE1 activity. The successful identification and optimization of these novel inhibitors could revolutionize cancer treatment by providing new options for combination therapies and overcoming resistance to existing treatments.
This project is a collaborative project between MEDCHEM.fi, UP-lab, and Aurlide Ltd.
M
G2
G1
S
Cell cycle arrest
WEE1
G2 checkpoint
Cancer cell continues to live
Normal
DNA-damage
M
G2
G1
S
Cell cycle continues with DNA damage
WEE1
G2 checkpoint
Cancer cell dies due to DNA damage
With WEE1 inhibitor
DNA-damage
Rational Development of Macrocyclic Compounds to Inhibit Triple-Mutant EGFR
Project Introduction
Epidermal Growth Factor Receptor (EGFR) mutations are frequently implicated in various cancers, with specific mutations leading to resistance against first- and second-generation EGFR inhibitors. The triple-mutant EGFR, particularly the T790M/C797S/L858R mutations, poses a significant challenge due to its enhanced oncogenic potential and resistance to conventional therapies. This project aims to rationally design and develop macrocyclic compounds that can effectively inhibit this triple-mutant EGFR variant. Utilizing a combination of structure-based drug design, molecular dynamics simulations, and high-throughput screening, we seek to identify macrocyclic inhibitors that can overcome the steric and kinetic challenges presented by these mutations. Our goal is to produce highly selective and potent inhibitors, offering a new therapeutic avenue for patients with resistant EGFR-mutant cancers.
This project is a collaborative project between MEDCHEM.fi and UP-lab.
EGFR mutations
1st and 2nd generation EGFR inhibitors
Cancer continues to grow due to resistance caused by EGFR mutations
EGFR mutations
Cancer can be treated with new therapies targeting specific EGFR mutations
KRAS
We develop small molecule modulators, targeted to two mutant forms of KRAS. If you are interested in collaborating with us, obtaining funding, and developing new treatments, contact us. Here is a reminder about the importance of these mutants...
Cancer drug discovery is a complex and dynamic field that involves the identification and development of drugs specifically designed to target and treat cancer. One of the crucial steps in this process is understanding the genetic alterations that drive cancer development and progression. Mutations in genes called oncogenes, such as KRAS, play a significant role in many types of cancer.
KRAS is one of the most frequently mutated oncogenes, and mutations in the KRAS gene are particularly common in several cancer types, including lung, pancreatic, and colorectal cancers. Two prevalent KRAS mutations are the KRAS G12V and G12D mutations. These mutations involve a single amino acid change (glycine to valine in G12V and glycine to aspartic acid in G12D) within the KRAS protein.
Targeting the KRAS G12V and G12D mutations is of great interest in cancer drug discovery for several reasons that are described next.
This project is a collaborative project between MEDCHEM.fi and UP-lab.
Prevalence
KRAS mutations, including G12V and G12D, are found in a significant proportion of cancer patients, making them attractive targets for therapeutic interventions. The frequency of KRAS mutations underscores the potential impact of developing drugs that specifically inhibit these mutations.
Oncogenicity
The G12V and G12D mutations in KRAS are known to confer increased oncogenic potential, leading to uncontrolled cell growth, proliferation, and survival. Consequently, targeting these specific mutations could disrupt the signaling pathways that drive cancer development, leading to improved treatment outcomes.
Lack of effective therapies
Despite the importance of KRAS mutations in cancer, developing effective drugs that directly target KRAS has been challenging. Traditional approaches to targeting proteins with small molecules have not been successful in inhibiting KRAS mutations. However, recent advancements have shown promise in developing targeted therapies against KRAS G12V and G12D mutations, making it an active area of research.
Therapeutic opportunities
The identification of specific vulnerabilities associated with KRAS G12V and G12D mutations opens up new therapeutic opportunities. Scientists are exploring various strategies, such as inhibiting KRAS downstream effectors or exploiting synthetic lethal interactions, to develop drugs that can selectively target cancer cells harboring these mutations while sparing normal cells.
The development of targeted therapies against KRAS mutations, including G12V and G12D, is an ongoing area of research and holds great potential for improving cancer treatment outcomes. Scientists and pharmaceutical companies are investing significant efforts in unraveling the complex biology of KRAS mutations and designing innovative therapeutic approaches to address the challenges associated with targeting these mutations.
TNFα
We develop macrocycle modulators, targeted to the tumor necrosis factor alpha (TNFα). Macrocycles could present a promising avenue in drug discovery for targeting TNFα due to several advantageous properties:
In summary, macrocycle ligands offer a promising solution for TNFα targeting in drug discovery due to their enhanced binding specificity, ability to engage challenging binding sites, improved pharmacokinetic properties, potential for oral availability, and cost-efficient discovery methods. These attributes make macrocycles an attractive option for developing novel therapeutics against TNFα and other challenging drug targets.
This project is a collaborative project between MEDCHEM.fi, UP-lab, and Aurlide Ltd.
Development of Macrocyclic Compounds Targeting α2β1 Integrin-Collagen Interaction
Project Description
Project Title: Rational Design and Development of Macrocyclic Compounds to Inhibit α2β1 Integrin-Collagen Interaction
Project Overview: This project aims to design and develop novel macrocyclic compounds that effectively inhibit the α2β1 integrin-collagen interaction. Building on our previous success with the small molecule inhibitor BTT-3033, we seek to leverage the unique properties of macrocycles to enhance selectivity, potency, and pharmacokinetic profiles. We aim to create new therapeutic agents for preventing and treating thrombotic diseases by targeting this interaction.
Background: The α2β1 integrin plays a crucial role in platelet adhesion and aggregation by mediating the binding of platelets to collagen in the vascular subendothelium. Dysregulation of this interaction contributes to pathological thrombosis, leading to conditions such as myocardial infarction, stroke, and deep vein thrombosis. While BTT-3033 has demonstrated efficacy in inhibiting this interaction, developing macrocyclic compounds offers several advantages, including improved binding affinity, enhanced specificity, and better pharmacokinetic properties.
Objectives:
Methodology:
Expected Outcomes:
Significance: Developing macrocyclic compounds targeting the α2β1 integrin-collagen interaction represents a novel and promising approach in anti-thrombotic therapy. Macrocycles offer the potential for superior drug-like properties, including enhanced selectivity and pharmacokinetics, which could translate into more effective and safer therapeutic options for patients at risk of thrombotic events. This project aims to expand our therapeutic arsenal and improve clinical outcomes in the management of thrombotic diseases.
Address
Contact information
Important links
Photo by Elisa Postila
@elisapostila