91桃色

Abstract

The current phosphodiesterase 4 subtype-b (PDE4b) inhibitors also inhibit its close subtype PDE4d resulting to severe adverse effects. It makes the selective inhibition of PDE4b a demanding task to design safe, next-generation drugs against asthma and inflammation. In the present study, crystal structure analysis was performed to distinguish the PDE4b and PDE4d selectivity on the basis of ligand binding. The analysis showed volume difference in the catalytic cavity regions of PDE4b and PDE4d. In addition to this, the position of key residue Tyr274 in PDE4b was reported to be occupied by Phe196 in PDE4d. Using the interactions profile of inhibitors with key residues, we developed a PDE4b selective pharmacophore to screen around 2.5 lakhs drug-like molecules from specs database. The top 1000 lead molecules were docked in PDE4b using Glide XP. The molecules that made H-bonds with Tyr274, Gln615, Hie450, His406, Tyr405, Asp564 or Asn455 were shortlisted. These shortlisted molecules bind with less affinity to other isoform when cross-docked in PDE4d structure. Also the molecules did not show any hydrogen bond in PDE4d. Future biological evaluation and further refinement of such PDE4b selective inhibitors would aid in development of new, anti-inflammatory drugs.

Biography

Vidushi Sharma is currently a PhD Scholar in Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), Department of Pharmaceutical Chemistry (affiliated to University of Delhi). She has completed Masters in Pharmaceutical Chemistry from DIPSAR and then she has worked as an Assistant Professor for about 2 years. She is presently working on DST funded project.

Email: vidushimaitry@gmail.com