Pharmacophore generation for human serotonin and human norepinephrine reuptake inhibitors
To gain a better understanding of biogenic amines, we carried out a pharmacophore analysis of known reuptake inhibitors and newly designed molecules with similar topology and chemical features. It is well understood that the clearance of biogenic amines from the synaptic cleft is achieved by a specific carrier transport system. Neurotransmitters and cotransported ions have been shown by several labs to be effective ligands that cause conformational changes in transporters. Inhibitors most likely block the conformational changes associated with the transport, and has found utility in the treatment of depression and other mental diseases. The neurotransmitter transporter contains approximately 600 amino acids and 12 transmembrane (TM) domains. Using molecular modeling techniques with the Catalyst software, fourteen training sets and two newly designed compounds with similar topology were built, and refined. The lowest energy conformers were used to generate a common feature pharmacophore (hypothesis) with HipHop. The features identified were hydrogen bond donor (HBD), hydrogen bond acceptor (HBA) and hydrophobic (HY). The human serotonin reuptake inhibitors (hSERT) hypothesis selected 10 hypothesis mapping three spheres- two HY regions and one HBA region. The human norepinephrine reuptake inhibitors (hNET) hypothesis selected 10 hypothesis mapping two spheres, one HBD, one HBA, and three HY. Two newly designed compounds named COS 101 and COS 105 were mapped to the hNET pharmacophore. The highest ranked hypothesis was used to mine two databases. The National Cancer Institute, (NCI) 238,819 compounds and Maybridge 54, 620 compounds. The compound 4-2-cloro-5-(triflurophenoxy)2-fluroaniline was retrieved from the Maybridge database as a Hit matching the hNET hypothesis. The Molinspiration chemoinformatics and Lipinski’s rules were calculated on this compound and it showed an mLogP value of 4.768 with zero violations.
Patrick C Brown,
"Pharmacophore generation for human serotonin and human norepinephrine reuptake inhibitors"
ETD Collection for Tennessee State University.