Acta Pharmacologica Sinica (2009) 30: 1694–1708; doi:10.1038/aps.2009.159

Acta Pharmacologica Sinica (2009) 30: 1694–1708; doi:10.1038/aps.2009.159; published online 23 Nov 2009

Original Article

Pharmacophore-based virtual screening versus docking-based virtual screening: a benchmark comparison against eight targets

Zhi CHEN¹, Hong-lin LI^2,*, Qi-jun ZHANG¹, Xiao-guang BAO¹, Kun-qian YU¹, Xiao-min LUO¹, Wei-liang ZHU¹, Hua-liang JIANG^1,2,*

¹Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China, ²School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

Aim:This study was conducted to compare the efficiencies of two virtual screening approaches, pharmacophore-based virtual screening (PBVS) and docking-based virtual screening (DBVS) methods.

Methods: All virtual screens were performed on two data sets of small molecules with both actives and decoys against eight structurally diverse protein targets, namely angiotensin converting enzyme (ACE), acetylcholinesterase (AChE), androgen receptor (AR), D-alanyl-D-alanine carboxypeptidase (DacA), dihydrofolate reductase (DHFR), estrogen receptors α (ERα), HIV-1 protease (HIV-pr), and thymidine kinase (TK). Each pharmacophore model was constructed based on several X-ray structures of protein-ligand complexes. Virtual screens were performed using four screening standards, the program Catalyst for PBVS and three docking programs (DOCK, GOLD and Glide) for DBVS.

Results: Of the sixteen sets of virtual screens (one target versus two testing databases), the enrichment factors of fourteen cases using the PBVS method were higher than those using DBVS methods. The average hit rates over the eight targets at 2% and 5% of the highest ranks of the entire databases for PBVS are much higher than those for DBVS.

Conclusion: The PBVS method outperformed DBVS methods in retrieving actives from the databases in our tested targets, and is a powerful method in drug discovery.

Keywords: pharmacophore; docking; LigandScout; enrichment; hit rate

We thank the Shanghai Supercomputing Center and Computer Network Information Center of Chinese Academy of Sciences for allocation of computing time. This work was supported by the National Natural Science Foundation of China (grants 20721003, 20803022, and 30672539), the International Collaboration Projects (grants 2007DFB30370 and 20720102040), the 863 Hi-Tech Program of China (grant 2007AA02Z304), and the State Key Program of Basic Research of China (grants 2009CB918502 and 2009CB918501).

* To whom correspondence should be addressed.
E-mail hlli@ecust.edu.cn or hljiang@mail.shcnc.ac.cn
Received 2009-06-23 Accepted 2009-09-27

[ Full text ]