TY - JOUR

T1 - PSW-Designer

T2 - An Open-Source Computational Platform for the Design and Virtual Screening of Photopharmacological Ligands

AU - Simon, Icaro A

AU - Homan, Evert J

AU - Wijtmans, Maikel

AU - Sundström, Michael

AU - Leurs, Rob

AU - De Esch, Iwan J P

AU - Zarzycka, Barbara A

PY - 2023

Y1 - 2023

N2 - Photoswitchable (PSW) molecules offer an attractive opportunity for the optical control of biological processes. However, the successful design of such compounds remains a challenging multioptimization endeavor, resulting in several biological target classes still relatively poorly explored by photoswitchable ligands, as is the case for G protein-coupled receptors (GPCRs). Here, we present the PSW-Designer, a fully open-source computational platform, implemented in the KNIME Analytics Platform, to design and virtually screen novel photoswitchable ligands for photopharmacological applications based on privileged scaffolds. We demonstrate the applicability of the PSW-Designer to GPCRs and assess its predictive capabilities via two retrospective case studies. Furthermore, by leveraging bioactivity information on known ligands, typical and atypical strategies for photoswitchable group incorporation, and the increasingly structural information available for biological targets, the PSW-Design will facilitate the design of novel photoswitchable molecules with improved photopharmacological properties and increased binding affinity shifts upon illumination for GPCRs and many other protein targets.

AB - Photoswitchable (PSW) molecules offer an attractive opportunity for the optical control of biological processes. However, the successful design of such compounds remains a challenging multioptimization endeavor, resulting in several biological target classes still relatively poorly explored by photoswitchable ligands, as is the case for G protein-coupled receptors (GPCRs). Here, we present the PSW-Designer, a fully open-source computational platform, implemented in the KNIME Analytics Platform, to design and virtually screen novel photoswitchable ligands for photopharmacological applications based on privileged scaffolds. We demonstrate the applicability of the PSW-Designer to GPCRs and assess its predictive capabilities via two retrospective case studies. Furthermore, by leveraging bioactivity information on known ligands, typical and atypical strategies for photoswitchable group incorporation, and the increasingly structural information available for biological targets, the PSW-Design will facilitate the design of novel photoswitchable molecules with improved photopharmacological properties and increased binding affinity shifts upon illumination for GPCRs and many other protein targets.

KW - Retrospective Studies

KW - Receptors, G-Protein-Coupled/chemistry

KW - Ligands

U2 - 10.1021/acs.jcim.3c01050

DO - 10.1021/acs.jcim.3c01050

M3 - Journal article

C2 - 37831965

VL - 63

SP - 6696

EP - 6705

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 21

ER -