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  • Matricon, PierreUppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för cell- och molekylärbiologi (author)

Structure-based virtual screening discovers potent and selective adenosine A1 receptor antagonists

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • Elsevier BV,2023
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-508538
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-508538URI
  • https://doi.org/10.1016/j.ejmech.2023.115419DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A1 and A2A adenosine receptors (A1R and A2AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. A library of 4.6 million compounds was screened computationally against both receptors using molecular docking and 20 A1R selective ligands were predicted. Of these, seven antagonized the A1R with micromolar activities and several compounds displayed slight selectivity for this subtype. Twenty-seven analogs of two discovered scaffolds were designed, resulting in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. Our results show the potential of structure-based virtual screening to guide discovery and optimization of subtype-selective ligands, which could facilitate the development of safer drugs.

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  • Nguyen, Anh T. N.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia. (author)
  • Vo, Duc DuyUppsala universitet,Institutionen för cell- och molekylärbiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)ducvo101 (author)
  • Baltos, Jo-AnneMonash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia. (author)
  • Jaiteh, MariamaUppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab(Swepub:uu)marja161 (author)
  • Luttens, Andreas,1993-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för cell- och molekylärbiologi(Swepub:uu)andlu970 (author)
  • Kampen, StefanieUppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för cell- och molekylärbiologi(Swepub:uu)steka514 (author)
  • Christopoulos, ArthurMonash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia. (author)
  • Kihlberg, JanUppsala universitet,Organisk kemi(Swepub:uu)janki643 (author)
  • May, Lauren ThereseMonash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia. (author)
  • Carlsson, JensUppsala universitet,Institutionen för cell- och molekylärbiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)jecar425 (author)
  • Uppsala universitetScience for Life Laboratory, SciLifeLab (creator_code:org_t)

Related titles

  • In:European Journal of Medicinal Chemistry: Elsevier BV2570223-52341768-3254

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