Strategies for generating less toxic P-selectin inhibitors: pharmacophore modeling, virtual screening and counter pharmacophore screening to remove toxic hits.
This paper describes the generation of ligand-based as well as structure-based models and virtual screening of less toxic P-selectin receptor inhibitors. Ligand-based model, 3D-pharmacophore was generated using 27 quinoline salicylic acid compounds and is used to retrieve the actives of P-selectin. This model contains three hydrogen bond acceptors (HBA), two ring aromatics (RA) and one hydrophobic feature (HY). To remove the toxic hits from the screened molecules, a counter pharmacophore model was generated using inhibitors of dihydrooratate dehydrogenase (DHOD), an important enzyme involved in nucleic acid synthesis, whose inhibition leads to toxic effects. Structure-based models were generated by docking and scoring of inhibitors against P-selectin receptor, to remove the false positives committed by pharmacophore screening. The combination of these ligand-based and structure-based virtual screening models were used to screen a commercial database containing 538,000 compounds.
Ananthula
Ravi Shekar
RS
BioCampus, GVKBIO S-1, Phase-1, Technocrats Industrial Estate, Balanagar, Hyderabad, Andhra Pradesh 500037, India.
Ravikumar
Muttineni
M
Pramod
A B
AB
Madala
Kishore Kumar
KK
Mahmood
S K
SK
D004353:Drug Evaluation, Preclinical; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D019007:P-Selectin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D019007:P-Selectin