Day 1 :
Universidad de Santiago de Compostela
Keynote: Covalent inhibition of bacterial type I dehydroquinase – Opportunities for anti-virulence therapies
Time : 10:00-10:00
Concepción González-Bello has obtained her PhD at the University of Santiago de Compostela (USC, Spain) in 1994. She did two predoctoral stays in thernUniversity of Gent (Belgium) with Prof. Vandewalle and in the Scripps Research Institute (USA) with Prof. Nicolaou. After a postdoctoral stay in the University ofrnCambridge (UK) with Prof. Abell, she joined USC as an Assistant Professor, and was promoted to Associate Professor in 2003 and obtained the Spanish habilitationrnto full Professor in 2011. In 2011, she joined the CIQUS, a new USC research center, as a group leader. She is author of about 70 papers and several patents andrnbook chapters.
The loss of effectiveness of current antibiotics caused by the development of drug resistance, along with the evident decline in antibiotic research by the major pharmaceutical companies during the last 50 years, has triggered the search for novel antibiotics and alternative therapies. Targeting bacterial virulence is an attractive choice that is increasingly being explored. The inhibition of virulence factors will lead to a loss of the ability of bacteria to cause infection in the host and, as a consequence they could be more easily eliminated by the immune system. A promising target for the development of new anti-virulence agents is the type I dehydroquinase enzyme (EC 188.8.131.52, aroD gene, DHQ1). This enzyme does not have any counterpart in human cells and seems to act as a virulence factor in vivo as the deletion of the aroD gene has been proven to afford satisfactory live oral vaccines. In this talk, several irreversible inhibitors of this enzyme that cause the covalent modification of the DHQ1rnfrom Salmonella typhi and Staphylococcus aureus and that are able to reduce the ability of Salmonella enteritidis to kill A459rnrespiratory cells will be presented. The resolution of diverse crystal structures of DHQ1 from Salmonella Typhi chemically modified by those compounds, the detection by mass spectroscopy of the reaction intermediates, in conjunction with the results of molecular dynamics simulations, allowed us to explain the inhibition mechanism of those compounds. Our recent results on this project will be presented
Keynote: Bridging the Dimensions: How 2D Structure-activity Relationships and 3D Structural Binding Affinity help to Guide Medicinal Chemistry
Time : 10:30-11:00
Carsten Detering obtained his PhD in Physical Chemistry from the Freie Universitaet Berlin in Germany in 2001. He did his Post Doc at the University of Washingtonrnin Seattle where he worked on the application of docking software for nucleic acid drug targets and rational design of new inhibitors for a malaria project. In 2005 herncame to BioSolveIT in Germany as an Application Scientist first, later filling the position of Senior Key Account Manager and Executive VP of Sales, North America,rnbefore moving back to Seattle as CEO of BioSolveIT Inc, the North American subsidiary of BioSolveIT.
The borders between traditional medicinal chemists and computational chemists have been blurred in the past 10 years. Medicinal chemists today are much more likely to assume more and more computational tasks. This entails crafting more intuitive software from the software industry, and also the seamless integration of 2D SAR data with 3D structural information to combine the medicinal chemist’s view of things with that of the computational chemist. This talk will highlight how we can utilize information from 2D ADME/T property models and 3D views of protein-ligand complexes. A glimpse into the near future will show how the influence of each atom or functional group on these properties can be highlighted and combined with visualization of the atomistic contributions to binding affinity. This enables development of optimization strategies that balance potency with the ADMET properties required in a safe and efficacious drug, thus giving this phase of the pipeline more efficiency by means of a truly multi-parameter optimization environment.