Current drug discovery collaborations are mainly centered on the high---throughput screening of large libraries of commercially available compounds. This fixed modality provides little opportunity for synergy between chemists and biologists. We seek to benefit from the increasing amount of structural information on protein---protein interactions (PPIs), exemplified by the Protein Data Bank (PDB), to embark in a PDB---wide systems biology approach that combines biophysical insights, multiple component reaction (MCR) chemistry, and advanced computer science to develop a radically new open---access technology that facilitates true collaboration between biologists who are experts on specific protein---protein interactions (PPIs) and chemists who have the expertise to design, discover and develop small molecular weight compounds. Our approach builds on the role of anchor side chains: side chains that are deeply buried in the acceptor protein of the PPI and identify well---defined "druggable" pockets. We use chemical mimicry of an anchor as an entry point into the rational design of MCR---accessible small molecular weight compounds. Contrary to traditional multistep sequential synthesis, MCR chemistry assembles advanced starting materials into a new product in a one---pot procedure resulting in a tremendous savings in cost and time. As a proof---of---concept, we have developed and validated a web---based technology that brings real---time rational drug design to the laptop of any scientist. Through a user---friendly interface, researchers can use their insights and expertise to design pharmacophores and screen millions of biased MCR---accessible compounds from over 20 distinct reactions in a matter of seconds. Using our approach we have obtained around a 50% hit rate when targeting the p53---MDM2 PPI.
Our specific aims are to: (a) expand the chemical space and targets covered by our libraries of novel, MCR---accessible virtual compounds;(b) improve the ranking, optimization and other analytical capabilities of our virtual screening technology;and (c) actively engage worldwide research groups with in vitro and/or in vivo assays with the goal of developing small molecular weight (ant)agonists. Based on the results of the virtual screening technology, we (or others) will be able to rapidly synthesize the predicted compounds. Our ultimate goal is to offer biomedical researchers direct access to virtual screening technologies and a limited number of potentially active novel compounds for them to use in their in---house small---scale screening capabilities. Active hits can then be optimized as chemical probes to study the functions of genes, cells, and biochemical pathways. This transformative resource is bound to lead to new ways to explore the functions of genes and signaling pathways in health and disease.
Current chemical biology collaborations are mainly based on high-throughput screening of large libraries of commercially existing compounds on targets of biological interest. However, this fix modality fails to provide much synergy between these two mature disciplines, i.e., chemistry and biology and often requires prior funding. We propose to develop a radically new open access technology to facilitate the true collaboration amongst biologists, say, experts on specific protein-protein interactions (PPIs) and chemists who are interested in the rational development of protein interaction small molecular weight (ant)-agonists. Specifically, we seek to benefit from the growing structural information on protein-protein interactions (PPIs), exemplified in the Protein Data Bank (PDB), to develop a PDB wide - sic system biology - approach that combine biophysical insights, multiple component reaction (MCR) chemistry to develop and screen million-size virtual libraries of chemically accessible novel compounds and potentiate small-scale lab assays with the ultimate goal to develop drugs for unmet medical needs, e.g. cancer, Alzheimer's and orphan diseases.
|Zhao, Ting; Kurpiewska, Katarzyna; Kalinowska-TÅ‚uÅ›cik, Justyna et al. (2016) Î±-Amino Acid-Isosteric Î±-Amino Tetrazoles. Chemistry 22:3009-18|
|Baumgartner, Matthew P; Camacho, Carlos J (2016) Choosing the Optimal Rigid Receptor for Docking and Scoring in the CSAR 2013/2014 Experiment. J Chem Inf Model 56:1004-12|
|Estrada-Ortiz, Natalia; Neochoritis, Constantinos G; DÃ¶mling, Alexander (2016) How To Design a Successful p53-MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures. ChemMedChem 11:757-72|
|Tejero, JesÃºs; Kapralov, Alexandr A; Baumgartner, Matthew P et al. (2016) Peroxidase activation of cytoglobin by anionic phospholipids: Mechanisms and consequences. Biochim Biophys Acta 1861:391-401|
|Ye, Zhaofeng; Baumgartner, Matthew P; Wingert, Bentley M et al. (2016) Optimal strategies for virtual screening of induced-fit and flexible target in the 2015 D3R Grand Challenge. J Comput Aided Mol Des 30:695-706|
|Hain, Ethan; Camacho, Carlos J; Koes, David Ryan (2016) Fragment oriented molecular shapes. J Mol Graph Model 66:143-54|
|Travers, Timothy S; Harlow, Lisa; Rosas, Ivan O et al. (2016) Extensive Citrullination Promotes Immunogenicity of HSP90 through Protein Unfolding and Exposure of Cryptic Epitopes. J Immunol 197:1926-36|
|Patil, Pravin; de Haan, Michel; Kurpiewska, Katarzyna et al. (2016) Versatile Protecting-Group Free Tetrazolomethane Amine Synthesis by Ugi Reaction. ACS Comb Sci 18:170-5|
|Eleftheriadis, Nikolaos; Poelman, Hessel; Leus, Niek G J et al. (2016) Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties. Eur J Med Chem 122:786-801|
|Chandgude, Ajay L; DÃ¶mling, Alexander (2016) An Efficient Passerini Tetrazole Reaction (PT-3CR). Green Chem 18:3718-3721|
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