Weinstein JN, Raghavan K, Buolamwini J, Zaharevitz D, Paull KD, Mazumder A, Fesen M, Kohn KW, Pommier Y; NIH Conference on Retroviral Integrase.
NIH Conf Retroviral Integr NIH Conf Retroviral Integr 1995 Bethesda Md. 1995 Jan 19-20; (Participants' abstracts and posters, abstract no. 11).
Lab of Molecular Pharmacology and Information Technology Branch, Developmental Therapeutics Program, DCT, NCI, Bethesda, Md.
The aim of this study was to identify new compounds active against the HIV-1 integrase using as a guide the hypothesis (Fesen, et al., Biochem. Pharmacol., in press) that ortho-OH groups favor inhibition (of both the cleavage and integration steps). Fesen, et al. (PNAS 90:2399, 1993) have identified inhibitors of this enzyme as potential therapeutic agents for AIDS. An assay using recombinant HIV-1 integrase and oligonucleotides identified 15 flavone analogues active against the enzyme at <100 micro M. We analyzed those molecules (and in some cases a total of 44) by 3 different quantitative structure-activity relationship (QSAR) methods: comparative molecular field analysis (CoMFA), electrotopological state (E-state) analysis, and back-propagation neural networks. To identify new inhibitors, we also developed a set of pharmacophoric descriptors in Chem-X and searched the NCI database of 400,000 3-D structures. Compounds predicted to be active are being tested in the integrase assay and in the NCI AIDS drug screen in CEM-SS cells. CoMFA, E-state, and neural network analyses all support the ortho-OH hypothesis. OH substituents at positions C5, C6, C31, and/or C5' appear favorable. When a flavanone molecule without ortho hydroxyls was found to inhibit the integrase, it was built and analyzed in the Sybyl molecular modeling package. In one of its lowest-energy states, the molecule folds on itself so that its two phenolic rings pi-pi stack with 2.78- separation between OH centers -- in good agreement with the 2.79- separation between ortho OH groups. Searches of the NCI database for molecules similar to the flavone, to the flavanone, and to the other inhibitors of the integrase yielded compounds that are currently being tested for activity. In conclusion, molecular structure analysis, 3-D structural database searching, and experimental assays can be combined to identify new potential inhibitors of the HIV- 1 integrase. Work of J.N.W. and Y.P. supported in part by the NIH Intramural AIDS Targeted Antiviral Program.
Publication Types:
Keywords:
- Computer Simulation
- Flavanones
- Flavones
- Flavonoids
- HIV Integrase
- HIV Integrase Inhibitors
- Integrases
- Models, Chemical
- Models, Molecular
- Molecular Conformation
- Molecular Structure
- Quantitative Structure-Activity Relationship
- diagnosis
- flavanone
- flavone
- organization & administration
Other ID:
UI: 102212978
From Meeting Abstracts