Discovery of potential ZAP-70 kinase inhibitors: pharmacophore design, database screening and docking studies.
The best ZAP-70 inhibitor model consists of four-pharmacophore features, (1) one hydrogen bond acceptor, (2) one hydrogen bond donor (3) one hydrophobic aliphatic and (4) one hydrophobic aromatic features. This model was validated against 110 known ZAP-70 inhibitors with a correlation of 0.902 as well as enrichment factor of 1.61 against a maximum value of 2. This model picked 4094 hits from a database of 238,819 molecules while 358 molecules were indicated as highly active. Subsequently, docking studies were performed on the hits and novel series of potent leads were suggested based on the interactions energy between ZAP-70 and the putative inhibitors which validated not only the virtual screening potential of the model but also identified the possible new Chemotypes.
Sanam
Ramadevi
R
GVK Biosciences Pvt. Ltd., Informatics Division, S-1, Phase-1, T.I.E. Balanagar, Hyderabad, Andhra Pradesh 500037, India. ramadevi.sanam@gvkbio.com
Vadivelan
S
S
Tajne
Sunita
S
Narasu
Lakshmi
L
Rambabu
G
G
Jagarlapudi
Sarma A R P
SA
D003198:Computer Simulation; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D051746:ZAP-70 Protein-Tyrosine Kinase