Combinatorial Pharmacophore Modeling of Multidrug and Toxin Extrusion Transporter 1 Inhibitors: a Theoretical Perspective for Understanding Multiple Inhibitory Mechanisms.
A combinatorial pharmacophore (CP) model for Multidrug and toxin extrusion 1 (MATE1/SLC47A1) inhibitors was developed based on a data set including 881 compounds. The CP model comprises four individual pharmacophore hypotheses, HHR1, DRR, HHR2 and AAAP, which can successfully identify the MATE1 inhibitors with an overall accuracy around 75%. The model emphasizes the importance of aromatic ring and hydrophobicity as two important structural determinants for MATE1 inhibition. Compared with the pharmacophore model of Organic Cation Transporter 2 (OCT2/ SLC22A2), a functional related transporter of MATE1, the hypotheses of AAAP and PRR5 are suggested to be responsible for their ligand selectivity, while HHR a common recognition pattern for their dual inhibition. A series of analysis including molecular sizes of inhibitors matching different hypotheses, matching of representative MATE1 inhibitors and molecular docking indicated that the small inhibitors matching HHR1 and DRR involve in competitive inhibition, while the relatively large inhibitors matching AAAP are responsible for the noncompetitive inhibition by locking the conformation changing of MATE1. In light of the results, a hypothetical model for inhibiting transporting mediated by MATE1 was proposed.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Yuan
Y
Xu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Xian
X
Liu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Yulan
Y
Wang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Nannan
N
Zhou
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Jianlong
J
Peng
Center for drug safety evaluation and research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Likun
L
Gong
Center for drug safety evaluation and research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Jing
J
Ren
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Cheng
C
Luo
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Xiaomin
X
Luo
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.|School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
Hualiang
H
Jiang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.|School of Life Science and Technology, Shanghai Tech University, Shanghai 200031, China.
Kaixian
K
Chen
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Mingyue
M
Zheng
D020650:Combinatorial Chemistry Techniques; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008970:Molecular Weight; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D008024:Ligands; D027701:Organic Cation Transport Proteins