Druggability assessment of mammalian Per–Arnt–Sim [PAS] domains using computational approaches

摘要: Per-Arnt-Sim (PAS) domains are key regions that occur in different regulatory proteins from all kingdoms of life. PAS show a remarkably conserved structural scaffold, despite highly variable primary sequence. In this study we have attempted to address some the gaps knowledge regarding druggability PAS-A domains, differences structure and dynamics within domain family how affects potential, as well give insight into steroid receptor coactivators putative binding modes NCOA1. Investigations were performed through range computational methods including molecular docking studies, atomistic simulations, hotspot mapping. Atomistic simulations function AhR PAS-B is regulated by tyrosine Y322 residue, which acts "gatekeeper" controlling access cavity finely tuning affinity. Furthermore, transition between partially unfolded helical conformation loop1 segment was shown be essential for generation "druggable" sites, especially NCOA1 domain. Finally, our indicated undruggability caused inherent characteristics their sites. conclusion, work emphasises role intrinsic shows coactivators, such NCOA1, can targeted small molecule ligands, highlights potential developing new therapeutics designed target these using structure-based approaches.