Skoči na glavni sadržaj

ADMET and DMPK, Vol. 9 No. 4, 2021.

Izvorni znanstveni članak

https://doi.org/10.5599/admet.1037

Are we ready to design oral PROTACs®?

Diego Garcia Jimenez ; University of Torino, Molecular Biotechnology and Health Sciences Dept., CASSMedChem, via Quarello 15, 10135 Torino, Italy
Jimenez, Matteo Rossi Sebastiano ; University of Torino, Molecular Biotechnology and Health Sciences Dept., CASSMedChem, via Quarello 15, 10135 Torino, Italy
Giulia Caron ; University of Torino, Molecular Biotechnology and Health Sciences Dept., CASSMedChem, via Quarello 15, 10135 Torino, Italy
Giuseppe Ermondi ; University of Torino, Molecular Biotechnology and Health Sciences Dept., CASSMedChem, via Quarello 15, 10135 Torino, Italy

Puni tekst: engleski pdf 1.348 Kb

str. 243-254

preuzimanja: 638

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Sažetak

PROTACs® are expected to strongly impact the future of drug discovery. Therefore, in this work we firstly performed a statistical study to highlight the distribution of E3 ligases and POIs collected in PROTAC-DB, the main online database focused on degraders. Moreover, since the emerging technology of protein degradation deals with large and complex chemical structures, the second part of the paper focuses on how to set up a property-based design strategy to obtain oral degraders. For this purpose, we calculated a pool of seven previously ad hoc selected 2D descriptors for the 2258 publicly available degraders in PROTAC-DB (average values: MW= 972.9 Da, nC= 49.5, NAR= 4.5, PHI= 17.3, nHDon= 4.5, nHAcc= 17.7 and TPSA= 240 Å2) and compared them to a dataset of 50 bRo5 orally approved drugs. Then, a chemical space based on nC, PHI and TPSA was built and subregions with optimal permeability and bioavailability were identified. Bioavailable degraders (ARV-110 and ARV-471) tend to be closer to the Ro5 region, using mainly semi-rigid linkers. Permeable degraders, on the other hand, are placed in an average central region of the chemical space but chameleonicity could allow them to be located closer to the two Arvinas compounds.

Ključne riječi

Degrader; bRo5; Bioavailability; Permeability; Chemical space; PROTAC-DB; Chameleonicity

Hrčak ID:

268286

URI

https://hrcak.srce.hr/268286

Datum izdavanja:

15.12.2021.

Posjeta: 1.995 *