J Chem Inf Model - Experimentally validated HERG pharmacophore models as cardiotoxicity prediction tools.

Tópicos

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Resumo

The goal of this study was to design, experimentally validate, and apply a virtual screening workflow to identify novel hERG channel blockers. The hERG channel is an important antitarget in drug development since cardiotoxic risks remain as a major cause of attrition. A ligand-based pharmacophore model collection was developed and theoretically validated. The seven most complementary and suitable models were used for virtual screening of in-house and commercially available compound libraries. From the hit lists, 50 compounds were selected for experimental validation through bioactivity assessment using patch clamp techniques. Twenty compounds inhibited hERG channels expressed in HEK 293 cells with IC50 values ranging from 0.13 to 2.77 ?M, attesting to the suitability of the models as cardiotoxicity prediction tools in a preclinical stage.

Resumo Limpo

goal studi design experiment valid appli virtual screen workflow identifi novel herg channel blocker herg channel import antitarget drug develop sinc cardiotox risk remain major caus attrit ligandbas pharmacophor model collect develop theoret valid seven complementari suitabl model use virtual screen inhous commerci avail compound librari hit list compound select experiment valid bioactiv assess use patch clamp techniqu twenti compound inhibit herg channel express hek cell ic valu rang m attest suitabl model cardiotox predict tool preclin stage

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