ABOUT
IPDD focuses on various aspects of pharmacology, going from structure-based drug design of both small molecules and macromolecular drugs to their interplay with tissue and its formulation. For this we will in particular investigate macromolecular drugs such as antibodies. The structure-function relationship of human drug target proteins and tissue will be explored both in vitro, ex vivo, and in vivo, utilizing X-rays at and neutrons.
CORE GROUP
GUEST RESEARCHERS
WORKING GROUPS FOR IPDD
IPDD WorkING Group 1
Structure-based drug design
Structure-based drug design aims to use structural biology methods to understand the molecular recognition and binding of potential drug compounds by their target proteins. X-ray crystallography is by far the most used method for this purpose, though neutron crystallography is crucial when the understanding of ligand-protein interactions requires us to investigate hydrogen atoms in the structure. Moreover, with an ever-increasing advancement of cryo-EM methods, high enough resolution can be achieved for some targets to study ligand binding without having to first crystallize the protein. Thus, although the focus of the current working group will be to resolve the details of how drugs interact with targets, method wise it will build on the previous successful LINXS theme “Integrative Structural Biology (ISB)”, by utilizing an integrative approach and make use of several structural biological methods to achieve the goals.
While structural models of the complexes between the ligand and the drug target provide necessary information for drug development, in order to achieve this purpose, expertise from different fields is required. Besides structural techniques and infrastructure, molecular pharmacology, chemical biology, medicinal, organic and computational chemistry all have to be employed for new molecule design, modification and understanding of their pharmacological properties at the drug targets of interest. Therefore the working group on structure-based drug design gathers scientists to represent all aspects of the topic:
- structural biology of soluble and membrane proteins
- chemical biology
- medicinal chemistry and organic synthesis
IPDD WORKING GROUP 2
Macromolecular Drugs –Antibodies
The research program “Antibodies in solution” was previously part of the “Dynamics theme” and has now transferred to the new “Integrative pharmacology and drug discovery” theme. This way, LINXS can continue to provide the optimal platform to gather researchers from different fields to work on this important and timely topic and help this bottom-up initiative to grow.
The mission of the “Macromolecular Drugs – Antibodies” working group in a nutshell is to provide a framework for a concerted experimental and theoretical research effort from leading research groups with complementary expertise to advance our understanding of antibody solutions. This will be achieved by bringing together leading research groups in the field, provide them with sufficient well-defined material, and coordinate the research activities of the individual groups in order to achieve the main research objectives outlined in detail in the Research Road Map.
The complexity of antibody solutions requires experimental information, theoretical models and simulations that cover a large range of characteristic length and time scales, which are accessible only through a combination of neutron- and Xray based techniques together with complementary methods. This can only be achieved through a collaborative effort, combining state of the art experimental, theoretical and simulation methods, and by carefully defining appropriate model systems that allow us to disentangle the various contributions and mechanisms that determine the solution properties.
Ipdd WORKING GROUP 3
Biomedical Imaging
The working group Biomedical Imaging aims to facilitate the use of imaging from MAX IV and ESS for drug discovery and development. Imaging of tissue ex-vivo as well as in-vivo imaging will be within the scope. Small animal imaging techniques by means of computed tomography, magnetic resonance imaging and various methods based on radioactive tracers including Positron Emission Tomography are already working tools for preclinical research in the pharmaceutical industry. These imaging techniques also are well represented at the core facility Lund University Bioimaging centre (LBIC). Thereby, studies performed on MAX IV or ESS can be supplemented by other imaging methods at LBIC.
MAX IV enables high spatial resolution imaging of intact tissue with details otherwise only depicted in histopathological slides, for which the latter only can be made on extracted thin tissue samples. Synchrotron radiation also provides phase-contrast X-ray imaging. For in-vivo the spatial resolution is governed by the animal experimental set-up (physiological motion) rather than the beam and detector properties. However, the high brilliance of MAX IV enables imaging at a unique high temporal resolution, which to some extent can compensate for the effects of physiological motion.
Synchrotron imaging can be used to increase the basic understanding of how tissue changes are related to diseases, which is of interest for pharmaceutical research. For example, X-ray phase contrast holographic nano tomography to visualize human myelinated nerve fibers and their subcomponents in 3D, characterization of atherosclerotic plaques, osteoporosis, or characterization of plexiform lesions in lung tissue for patients with pulmonary hypertensions.
In-vivo imaging can be used to assess the direct effect of a drug, such as drugs for asthma by estimation ventilation in lungs. With the high spatial resolution it is also possible to image atelectrauma at an alveolar resolution in ventilator-induced lung injury in animals. In contrast to X-rays, neutrons can penetrate metal and bone easily but are attenuated by water and organic materials. Biomedical imaging using neutrons is not so well explored, but due to the specific properties of neutrons, imaging of soft tissues with high spatial resolution is possible.
IPDD WORKING GROUP 4
BIOPHYSICS OF DRUG DELIVERY
The “Biophysics of Drug Delivery” working group aims at developing orthogonal approaches for designing and characterizing efficient drug delivery systems, from pharmaceutical formulation development to the design of novel materials. The challenge is represented by the need of bringing together scientists with different backgrounds with the aim of creating an interdisciplinary platform to efficiently face the main obstacles preventing the drugs to reach the target. The group will focus on combining neutrons and X-rays sciences with imaging and spectroscopic approaches and try to foster a novel culture in the pharmaceutical sciences.
IPDD Core Group Leader and Integrative Structural Biology Core Group Leader, LINXS Fellow
Karin Lindkvist is an expert in structural biology in particular applying X-ray crystallography. Her research encompasses both structural studies of integral membrane proteins and soluble proteins, in particular proteins important in human metabolism such as glucose transporters and glycerol channels. Lindkvist has a strong scientific network in the field of membrane protein structural biology.