Medicinal Chemistry & Systems Polypharmacology

Research Team

Principal Investigator
Sven Marcel Stefan, Dr. rer. nat., M. Sc., Pharmacist (Germ. ‘Apotheker’)

PANABC Co-Leaders (DFG # 504079349)
Vigneshwaran Namasivayam, PhD, MTech, BTech
Hauke Busch, PhD

Postdoctoral Fellows
Gergely Gyimesi, PhD
Katja Stefan, Dr. rer. nat., M. Sc., B. Sc.

Master's Students
Ahmed Abdelhamid

Bachelor's Students
Katrin Kuner

Research Agenda

The Medicinal Chemistry and Systems Polypharmacology group provides feasible solutions to tackle current questions in medicinal chemistry by focusing on rational development of small-molecule drugs, elucidating the chemical biology of drug-target interactions, establishing novel spectroscopic and spectrometric frameworks and assay workflows, as well as discovering structurally novel and functionally distinctive bioactive agents with advanced computational prediction methodologies. The interdisciplinary character of the group synthesizes individual skills to advance in medicinal chemistry, chemical biology, and molecular pharmacology, particularly:

Medicinal Polypharmacology
Acquisition, comprehension, and utilization of polypharmacological drug profiles to gain an improved data awareness of drug polypharmacology. These information serve several purposes, such as accurate risk assessments including adequate safety measures of currently approved or developed drugs, extended indications of drugs as part of modern drug repurposing strategies, intentional engagement of multiple targets as valid therapeutic options to tackle multifactorial diseases, as well as development of truly selective, highly specific drugs, diagnostics, and tool compounds.

Target (Class) Repurposing
Translation of gained knowledge about well-studied, individual drug targets or entire target classes toward an unknown target landscape to explore and exploit potential pharmacological targets of the future. Target (class) repurposing is a common term in antiinfective research that the group translates into other fields of medical research for the identification of novel bioactive agents to address both prevalent and rare human diseases.

Translation between Species
Identification of distinctive features of phylogenetically linked orthologs of various species that serves both the development of drugs against species other than humans (i.e., antibiotics, antivirals, antifungals, anthelmintics, etc.,) as well as the improvement of currently used animal models (e.g., mouse, rat, etc.) in pre-clinical drug assessments.

Deorphanization, Target Identification / Validation, and Druggability
Structural, functional, and pharmacological analyses of newly identified and/or yet under-studied (‘orphan’) drug targets to explore and exploit them as potential therapeutic drug targets of the future. The group anticipates the development of chemically diverse (potential) interactors to (identify and) validate orphan targets and their evolution to novel tracers and modulators. In addition, biotechnological and cell-biological methodologies are applied to establish orphan target-linked phenotypes and novel living cells-based assessment platforms.

Scientific Questions Addressed

The Medicinal Chemistry and Systems Polypharmacology group envisions the identification of key aspects of polypharmacology and the ‘polypharmacolome’, particularly the elucidation, characterization, complete description, as well as exploitation of polypharmacological coherences in their entirety in the fields of:

Structural Polypharmacology
The existence of ‘superfolds’ and ‘supersites’ as re-occurring structural motifs within phylogenetically and/or functionally distant proteins inspired the group to study ‘multitarget binding sites’ between related and unrelated protein families to deduce general rules of polypharmacology.

Molecular Polypharmacology
Complementary to structural biology, the identification of molecular-structural motifs that promote (and impede) multitargeticity is in focus to address the question: What makes a multitarget agent a multitarget agent?

Evolutionary Polypharmacology
How advanced are the levels of distinction between distantly related protein orthologs, and how can structural commonalities be used to develop novel drugs against bacteria, fungi, viruses, nematodes, and other communicative diseases particularly in the context of recent pandemic events? And how can pre-clinical data be interpreted in the light of evolutionary differences?

Functional Polypharmacology
Complementary to systems biology approaches to identify novel players in multifactorial human diseases such as cancer, metabolic syndrome, or neurodegeneration, the group’s systems polypharmacology approach anticipates to comprehend causative target combinations and their pathophysiology, as well as the development of multitarget strategies to cure human disease.

Medicinal Polypharmacology
The group pioneers in this interdisciplinary work field between medicinal chemistry, chemical biology, and molecular pharmacology to promote the development of ‘polypharmaceuticals’ / ‘polypharmacologicals’ or entire high-quality compound collections of these ‘privileged ligands’ for integral multitarget strategies in modern therapy to tackle multi-factorial human diseases.

Clinical Polypharmacology
Retrospective analyses of approved drugs or drug candidates in clinical evaluation to expand opportunity space in future drug therapy.

Cutting-edge Techniques

Embedded in an interdisciplinary and translational work environment, the Medicinal Chemistry and Systems Polypharmacology group applies various techniques, including:

• Cheminformatic and bioinformatic procedures to generate and harness high-quality datasets by data mining
• Computational chemistry to structurally understand drug-target interactions (i.e., molecular docking, molecular dynamics, etc.) and to predict molecular-structurally distinctive and functionally novel bioactive agents by virtual screening of chemical space (i.e., pattern analysis, similarity search, pharmacophore modelling, etc.)
• Organic synthesis for structure-activity relationship elucidation, hit-to-lead optimization, and generation of novel tool compounds as well as potential therapeutics and diagnostics
• Chromatographic, spectroscopic, and spectrometric establishment of novel tracer molecules for orphan targets (e.g., HPLC, fluorometry, LC-MS, etc.).
• Biotechnological and cell-biological techniques to establish expression and function of (orphan) targets, particularly selection and/or transfection of target combinations including advanced cell culture and assay protocols
• Functional analyses (e.g., flow-cytometry) for drug effect characterization and establishment of novel assay workflows

The in-house cell-biology of the Medicinal Chemistry and Systems Polypharmacology group is specialized in the assessment and small-molecular engagement of ATP-binding cassette (ABC) and solute carrier (SLC) transporters. Together with the vast global, collaborative network, the functional analysis of 15 and 48 human ABC and SLC transporters, respectively, is performed, complemented by a number of non-human (e.g., canine, murine, rat, zebrafish, nematode, and bacterial) ABC and SLC transporters. Further information can be found at www.panabc.info and www.panslc.info.