6UM8
HIV Integrase in complex with Compound-14
Summary for 6UM8
| Entry DOI | 10.2210/pdb6um8/pdb |
| Descriptor | Integrase, PENTAETHYLENE GLYCOL, DI(HYDROXYETHYL)ETHER, ... (6 entities in total) |
| Functional Keywords | dna integration, aids, rnaseh, ledgf, endonuclease, hiv-1 integrase, transferase, hydrolase |
| Biological source | Human immunodeficiency virus 1 |
| Total number of polymer chains | 2 |
| Total formula weight | 38992.06 |
| Authors | Khan, J.A.,Kish, K. (deposition date: 2019-10-09, release date: 2020-03-04, Last modification date: 2023-10-11) |
| Primary citation | Li, G.,Meanwell, N.A.,Krystal, M.R.,Langley, D.R.,Naidu, B.N.,Sivaprakasam, P.,Lewis, H.,Kish, K.,Khan, J.A.,Ng, A.,Trainor, G.L.,Cianci, C.,Dicker, I.B.,Walker, M.A.,Lin, Z.,Protack, T.,Discotto, L.,Jenkins, S.,Gerritz, S.W.,Pendri, A. Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors. J.Med.Chem., 63:2620-2637, 2020 Cited by PubMed Abstract: The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine , which was optimized at the 2- and 7-positions to afford and as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties. PubMed: 32081010DOI: 10.1021/acs.jmedchem.9b01681 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.33 Å) |
Structure validation
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