Current Research:

The Doemling group is collaborating on several projects with groups in Israel, Germany, The Netherlands, Russia and Pittsburgh. Research in the Doemling group covers a broad spectrum of Chemistry & Biology, including
• Combinatorial and Multi Component Reaction Chemistry (MCR)
Multicomponent processes (reactions of three and more starting materials) are at a premium for the achievement of high levels of brevity and diversity, as they allow more than two simple and flexible building blocks to be combined in practical, time-saving one-pot operations. Due to their inherent simple experimental procedures and their one-pot character, they are perfectly suited for automated synthesis. Thus, MCRs have attracted considerable interest owing to their exceptional synthetic efficiency. The structure of the reaction product can easily be diversified by systematic variation of each input. Moreover, the starting materials are either commercially available or easy to prepare. Our group has had a long tradition in the discovery of new MCRs and its application to drug discovery questions and applications. A recent and comprehensive review is available for free.
 
• Protein Protein Interactions
Classical targets of drug discovery involve enzymes where medicinal chemists aim to design substrate and transition state analogues in a highly structure based approach. A recently emerging target area is protein protein interactions (PPI). PPIs play fundamental roles in almost every aspect of living cells. Small molecule (ant)agonists of PPIs are inherently difficult to design for several reasons. We use MCR chemistry, computational design and biophysical analysis to discover and investigate the interplay of small molecules with large protein protein interactions. Current targets involve p53/mdm2, XIAP, cyclin-binding groove, death receptor 5 and homo/heterodimeric enzymes.
 
• Anti Cancer Drugs
Several of our targets are cancer related, e.g. p53/mdm2, XIAP, cyclin-binding groove, death receptor 5 and tubulin. Our molecules are investigated in vitro and in vivo for their anti cancer activity.
 
• GPCR
GPCR targeting compounds make up more than 50 % of current drugs and they are commercially extremely successful. However, in-depth structural information is mostly not available due to the membrane nature of GPCRs. We use MCR pharmacophore analysis, homology modeling and MCR chemistry to design and discover new GPCR ligands. An intensively studied GPCR in our group is anxiety and depression related corticotrophin releasing factor receptor (CRFr).
 
• Natural Products
Natural products as opposed to synthetic small molecules encompass “barock” structures, highly enriched with stereochemistry and heteroatom functionality. However, unlike most small molecules, natural products are almost inevitably biologically highly active due to their evolutionary genesis. We are interested in the synthesis of natural products using convergent MCR strategy. Synthesis including MCR strategy allows for the efficient assembly of the natural product as well as its libraries and their biological investigation. Current targets are Tubulysin, Aspergillamide and actin binding natural products. Moreover we are interested in targeting approaches to render highly cytotoxic Tubulysin selective for malign tumors and useful as drug to fight cancer.
 
• Matched Molecular Pair Analysis
The optimization of a hit via a lead compound into an advanced drug candidate in pharmaceutical industry is an empirical process relaying on few “rules” and involving much “trial and error”. We investigate the pharmaceutical property change in pairs of molecules that differ only by a well-defined structural transformation. The aim is to broaden the “rule” basis for this lead optimization process by using “matched molecular pairs” analysis.
 

Bio:

Alexander Dömling (borne 1964 in Munich/Germany) studied Chemistry & Biology at the Technical University Munich (TUM). He performed his PhD under the surveillance of the late Ivar Ugi working on the “Seven Component Reaction”. As a Humboldt fellow he performed his postdoc in the laboratory of the Nobel laureate Barry Sharpless working on novel multicomponent reactions of hydrazines, epoxides and carboxylic acid derivatives. In 1996 he started the biotech company Morphochem and served as vice president chemistry and board member till 2004. During this time several drug candidates have been developed at Morphochem and are currently in late preclinical or clinical trials, e.g. the most advanced compound Almorexant® currently undergoes phase III clinical trials. Additionally he founded R&D Biopharmaceuticals. In 2003 he performed the Habilitation at the TUM and received the “Lehrerlaubniss in Chemie”. Since 2004 he is faculty member at the TUM. In 2006 he accepted an associate professor position in the School of Pharmacy (Drug Discovery Institute) at the University of Pittsburgh with a secondary appointment in the department of chemistry. Additionally, he is member of the University of Pittsburgh Cancer Center and teaching faculty of the Molecular Biophysics & Structural Biology (MBSB) program and Carnegie Mellon University / University of Pittsburgh joint Ph.D. Program in Computational Biology.