Acta Phys. -Chim. Sin. ›› 2007, Vol. 23 ›› Issue (09): 1325-1331.doi: 10.1016/S1872-1508(07)60067-9

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Pharmacophore Model Generation Based on Pyrrolidine- and Butane-derived CCR5 Antagonists

KONG Ren; XU Xue-Mei; CHEN Wei-Zu; WANG Cun-Xin; HU Li-Ming   

  1. College of Life Sciences and Bioengineering, Beijing University of Technology, Beijing 100022, P. R. China
  • Received:2007-04-19 Revised:2007-05-29 Published:2007-09-06
  • Contact: WANG Cun-Xin; HU Li-Ming;

Abstract: A three-dimensional pharmacophore model was developed for a considerable number of pyrrolidine-based and butane-based chemokine (C-C motif) receptor 5(CCR5) antagonists, which can block the entry of human immunodeficiency virus type 1 (HIV-1) by inhibiting the interaction of HIV-1 envelope protein and CCR5. The pharmacophore model was generated using a training set consisting of 25 carefully selected antagonists with the diverse molecular architecture and bioactivity, as required by the Catalyst/HypoGen program. The activity of the training set molecules expressed in IC50 ( half-inhibitory concentration) covered from 0.06 to 10000 nmol·L-1. The most predictive pharmacophore model (Hypo 1), consisting of two positive ionizable points and three hydrophobic groups, had a correlation of 0.924 and a root mean square of 1.068, and a cost difference of 63.67 bits between the null cost and the total cost. The model was applied in predicting the activity of 74 compounds as a test set. The results indicated that the model was able to provide clear guidelines and accurate activity prediction for novel antagonist design.

Key words: CCR5, HIV-1, Pharmacophore model, Ligand-based drug design


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