Construction and Application of Pharmacophore Model of BACE-1 inhibitors
A three-dimensional pharmacophore model has been constructed for evaluating and designing new BACE-1 inhibitors. A training set consisting of 74 BACE-1 inhibitors with six different classes of diverse structures were selected based on the structures and activity data as required by the HypoGen process in the Catalyst software. After molecular modeling, conformational analysis, and hypothesis generating, the best pharmacophore in terms of statistics and predictive value had four features: two hydrogen bond acceptors (HA), one hydrophobic (HP) feature, and one positive ionizable (PI) feature. It was selected with the highest cost difference, lowest error cost, lowest rms difference, and the best correlation coefficient (cost difference=160.437, error cost=274.066, rms=0.825, Correl=0.937, Config=19.986). It had perfect activity prediction ability and was validated on 36 test inhibitors, yielding a correlation coefficient of 0.951. Moreover, it revealed the ion-dipole bond between P4-site of OM992 and residues of BACE-1. The three-dimensional pharmacophore model provided some important information essential for binding interaction in the drug design process, and is potentially applicable as a useful tool to develop multi-target-directed ligands for Alzheimers disease treatment.
Wen-Ting Zhang Feng-Chao Jiang Bao-Shuai Cao Jin-Lan Ruan
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology The Key La
国际会议
武汉
英文
784-804
2010-09-01（万方平台首次上网日期，不代表论文的发表时间）