HIV-1 integrase pharmacophore model derived from diverse classes of inhibitors Gabriela Iurcu Mustata, a,y Alessandro Brigo b and James M. Briggs a, * a Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001, USA b Dipartimento di Scienze Farmaceutiche, Universita ` degli Studi di Padova, 35131 Padova, Italy Received 29 September 2003; revised 9 January 2004; accepted 14 January 2004 Abstract—A three-dimensional pharmacophore model has been generated for HIV-1 integrase (HIV-1 IN) from known inhibitors. A dataset consisting of 26 inhibitors was selected on the basis of the information content of the structures and activity data as required by the catalyst/HypoGen program. Our model was able to predict the activity of other known HIV-1 IN inhibitors not included in the model generation, and can be further used to identify structurally diverse compounds with desired biological activity by virtual screening. # 2004 Elsevier Ltd. All rights reserved. 1. Introduction Human immunodeficiency virus type 1 is the etiological agent of acquired immunodeficiency syndrome (AIDS). HIV encodes three enzymes: reverse transcriptase, pro- tease and integrase. Only the first two enzymes have been successfully exploited as targets for antiviral drugs. The emergence of strains resistant to currently available reverse transcriptase and protease inhibitors has led to the necessity to focus on new targets. An essential step in HIV replication is the integration of the transcribed double-stranded viral DNA into the host chromosomes which is carried out by HIV-1 integrase (IN). 2,3 Inte- gration occurs in two consecutive reactions: 4 in the first step, termed 3 0 -processing, an activated water molecule attacks each 3 0 -end of the viral DNA removing a dinu- cleotide from each; in the second step, called ‘strand transfer’, each exposed viral DNA 3 0 -OH ribose is acti- vated for nucleophilic attack on opposite strands of the host DNA, becoming covalently attached to them. Nucleophile activation occurs through the action of Mg 2+ ions in the active site. To date, a number of clas- ses of compounds have been identified to be active either against the 3 0 -processing or strand transfer, 5 13 but none of them have completed clinical trials because of their limited potency or high toxicity. In contrast to HIV-1 protease and reverse transcriptase, where a number of crystal structures of the enzyme–ligand complexes are available, HIV-1 IN is lacking the struc- tural information that would allow clear derivation of the important three-dimensional arrangements and the essential functional groups needed by a compound to effectively interact with the enzyme. Only one crystal structure of HIV-1 IN with a bound inhibitor (5CITEP) in the active site is currently available. 14 Despite the paucity of structural information at a molecular level about IN–inhibitor interactions, a con- siderable number of activity data for inhibitors that belong to diverse chemical classes is currently available. Several compounds such as dioxepinones, 5 quinones, 5 benzoic hydrazides, 7 thiazolothiazepines, 8 salicylpyr- azolinones, 9 coumarins, 11 etc., have been reported to inhibit integrase’s enzymatic activity at low micromolar concentrations. Pommier et al. have reported the devel- opment of pharmacophore models 15 18 derived from a series of HIV-1 IN inhibitors. These pharmacophore models were used to search the National Cancer Insti- tute three-dimensional (3D) Structural Database and some of those compounds were found to inhibit both 3 0 - processing and strand transfer of IN at micromolar concentrations. Recently, a series of compounds repre- senting a new class, typified by an aryl b-diketo motif (from the Merck laboratories), revealed very high activities and strong selectivity for the inhibition of the strand 0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.01.027 Bioorganic & Medicinal Chemistry Letters 14 (2004) 1447–1454 Keywords: HIV-1 integrase; Inhibitor design; Pharmacophore model. *Corresponding author. Tel.: +1-713-743-8366; fax: +1-713-743- 8351; e-mail: jbriggs@uh.edu y Present address: Emisphere Technologies, Inc., Tarrytown, NY 10591, USA.