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UID:930@biology.technion.ac.il

DTSTART;TZID=Asia/Jerusalem:20201202T130000

DTEND;TZID=Asia/Jerusalem:20201202T140000

DTSTAMP:20210802T125902Z

URL:https://biology.technion.ac.il/en/seminars/daniel-zaidman-phd-graduate
 -seminar-2/

SUMMARY:Daniel Zaidman-PhD Graduate Seminar [No Categories]
DESCRIPTION:Location:   \n Affiliation: \n Host:\n DanielZaidmanFrom the La
 b ofDr. Nir London  Weizmann Institute of Science  Computational protoc
 ols for thedesign of next generation chemical tools.Covalent irreversible 
 inhibitors\, andprotein degraders (PROTACs) are two emerging fields that a
 re growing rapidlyover the past decade. Such molecular modulators have sev
 eral advantagescompared to traditional drugs. Irreversible inhibitors have
  a longer residencetime\, time dependent inhibition\, and improved potency
 . PROTACs are alsoeffective at lower concentrations\, due to their catalyt
 ic effect\, and theirrecyclable nature. Yet\, both field suffer from lack 
 of computational tools forthe rational design of compounds. We developed c
 omputational protocols forthese two domains that are built on simple geome
 trically oriented schemes whichleverage the specific nature of the problem
 s at hand.        Inthe field of covalent and irreversible inhibitor
 s\, I will present – Covalentizer\, apipeline for turning reversible no
 n-covalent inhibitors into covalent ones\,based on a crystal structure of 
 the molecule bound to its target protein. Apublic database with prediction
 s against the entire protein data bank (PDB)\,including over 1500 covalen
 tized structureswas made available at https://covalentizer.weizmann.ac.i
 l/. Wetested the method retrospectively and successfully recapitulated kno
 wn covalentkinase inhibitors\, given only their reversible recognition ele
 ments.Furthermore\, selected candidates were synthesized and tested\, and 
 a few novelcovalent kinase inhibitors\, as well as an inhibitor for the SA
 RS-CoV-2 mainprotease were discovered [1].        Inthe field of PRO
 TACs\, I shall present the ProsettaC protocol\,which predicts ternary co
 mplexes between the degradation target\, the E3 ligaseand the PROTAC. This
  is achieved by alternating between the sampling of theprotein-protein int
 eraction space\, and the PROTAC molecular conformationalspace. It was used
  to recapitulate crystal structures with atomic accuracy\, aswell as prosp
 ectively predict a new ternary complex with high confidence [2].The method
  is available at https://prosettac.weizmann.ac.il/. Ina second project\, 
 by a group effort\, we created a public database of PROTACs\,which will be
  based on contributions and reviews from members of the entirePROTAC commu
 nity. It is available at https://protacdb.weizmann.ac.il/.  Thesetools\
 , combined with our efforts to make them publicly available\, should enabl
 ebroad access to new and improved chemical probes.  Zoomlink:https://weiz
 mann.zoom.us/j/98162721348  

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