Our next webinar will take place via the internet on Tuesday March 29th at 10 AM EST/3 PM GMT. Sign up on our mailing list to receive the Zoom link!
We hope to see/hear from you all at one of our sessions or as one of the next speakers. If you are an early career scientist and would like to present your research, don't hesitate to submit an abstract today! For now, please learn more about our current speakers and their research below. We also thank the generous support from Cell Reports Physical Science, Merck, Janssen, and the Royal Society of Chemistry.
Our featured speakers this week are Lilian Sophie Szych (Graduate Student, Universität Rostock, Germany), and Dr Sergio Ribone (Principal Investigator, National University of Córdoba, Argentina). The guest moderator is Dr Andrew Bissette from Cell Reports Physical Science.
LEARN MORE ABOUT THE SPEAKERS AND THEIR TALKS BELOW
LILIAN SOPHIE SZYCH (on Twitter @szych_lilian)
Biography: Lilian Szych studied chemistry at the University of Rostock, including an internship at Queens University in Canada. She continued at Rostock for her PhD under the supervision of Professor Axel Schulz on the synthesis and characterization of pnictogen compounds for the activation of small molecules. Following this, she is currently a postdoctoral fellow at the TU Braunschweig in the group of Professor Matthias Tamm, investigating N-heterocyclic carbenes. Beyond the lab, she enjoys participating in Science Slams and biking/hiking somewhere in the nature.
Title of Talk: "Synthesis and Investigation of Phosphane Pnictanyldithiocarboxylates"
Abstract: Phosphane-substituted pnictanyldithiocarboxylates (pnictogen = P, As) display interesting structural motifs. However, only a few examples have been reported so far, which were synthesized by conversion of sterically demanding diphosphanes or phosphaarsanes with CS2. However, this synthetic route is not universal but limited to the conversion of certain dipnictanes. The reactivity of a variety of diphosphanes and phosphaarsanes toward CS2 was investigated in detail, revealing a strong dependency on the substitution pattern of the dipnictanes as well as on steric and on electronic factors. To circumvent the limited product scope, a new synthetic route toward the desired species was developed, using the same starting materials, but in a different sequence. The alternate route includes the conversion of a secondary phosphide with CS2 to yield the corresponding phosphanyl dithiocarboxylate, which then can be converted with a secondary halopnictane to yield the desired products.
DR SERGIO RIBONE (on Twitter @quimeds)
Biography: My name is Sergio Ribone, I’m an Assistant Professor at National University of Córdoba (UNC), Córdoba, Argentina and a Junior Researcher from CONICET. After receiving my degree in Pharmaceutical Science, I did my PhD in the School of Chemical Science under the topic of drug design of novel NNRTI against HIV. My research interests are involved with the drug design of agents against different targets. In the past two years, with some colleagues at UNC, we formed a team to find new compounds that can be inhibitors against different SARS-CoV-2 targets, using a combination of molecular modeling strategies.
Title of Talk: "Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking"
Abstract: Screening already approved drugs for activity against a novel pathogen can be an important part of global rapid-response strategies in pandemics. Such experimental high-throughput repurposing screenings (HTRS) have already identified several existing drugs with potential to combat SARS-CoV-2. However, moving these hits forward for possible development into drugs specifically against this pathogen requires unambiguous identification of their corresponding targets, something the high-throughput screens are not typically designed to reveal. We present here a new computational inverse-docking (INDO) protocol that uses all-atom protein structures and a combination of docking methods to rank-order targets for each of several existing drugs for which a plurality of recent high-throughput screens detected anti-SARS-CoV-2 activity. We demonstrate validation of this method with 209 known drug-target pairs, including both non-antiviral and antiviral compounds. The combined scoring functions recover the correct ligand-protein complex 66%, 75% and 81% in the top-1, top-3 and top-5, respectively. From three independent already publish HTRS, the highly active repurposed drug (HARD) list were constructed with those compounds that were among the top 25% most active in at least two of the three HTRS studies. This list comprises 152 drugs that were subjected to the INDO procedure, plus 14 known inhibitors of different targets included in this study as control compounds (CC). 18 structural and non-structual viral proteins were selected for this study based on their roles in the viral life cycle and also on the availability of a three-dimensional structure. Because of their important role on the early stages of SARS-CoV-2 infection, 8 human protein/enzymes were also added as potential targets to the INDO procedure. The most common preferential targets were the human enzymes TMPRSS2 and PIKfyve, followed by the viral enzymes Helicase and Plpro. This observation is in line with the fact that enzymes are more druggable targets that any other non-structural or structural SARS-CoV-2 protein. The INDO methodology successfully identified 10 out of 14 CC in their top-3 preferences, showing good accuracy in identifying the correct SARS-CoV-2 protein/enzyme target. The analysis on the HARD showed that all the drugs that selected TMPRSS2 are known serine protease inhibitors, and those that selected PIKfyve are known tyrosine kinase inhibitors. Detailed structural analysis of the docking poses revealed important insights into why these selections arose, and could potentially lead to more rational design of new drugs against these targets. The results presented in this work contribute to the characterization of drugs with potential for directly repurposing against SARS-CoV-2 and to the further development of novel compounds with anti-SARS-CoV-2 activity.