Investigation of the molecular characteristics of bisindole inhibitors as HIV-1 glycoprotein-41 fusion inhibitors
| Autor: | Ariana Nemati, Shidong Chu, Guangyan Zhou, Roger G. Ptak, Beth A. Snyder, Miriam Gochin, Chunsheng Huang |
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| Rok vydání: | 2019 |
| Předmět: |
Indoles
Stereochemistry Ring (chemistry) 01 natural sciences Article Small Molecule Libraries Hydrophobic effect Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound HIV Fusion Inhibitors Drug Discovery Moiety IC50 030304 developmental biology Benzoic acid Pharmacology chemistry.chemical_classification Indole test 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry General Medicine Small molecule HIV Envelope Protein gp41 0104 chemical sciences chemistry Glycoprotein Hydrophobic and Hydrophilic Interactions |
| Zdroj: | European Journal of Medicinal Chemistry. 161:533-542 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.10.048 |
| Popis: | In previous work, we described 6–6’-bisindole compounds targeting a hydrophobic pocket on the N-heptad repeat region of viral glycoprotein-41 as effective inhibitors of HIV-1 fusion. Two promising compounds with sub-micromolar IC(50)’s contained a benzoic acid group and a benzoic acid ester attached at the two indole nitrogens. Here we have conducted a thorough SAR study evaluating the contribution of each of the ring systems and various substituents to compound potency. Hydrophobicity, polarity and charge were varied to produce 35 new compounds that were evaluated in binding, cell-cell fusion and viral infectivity assays. We found that (a) activity based solely on increasing hydrophobic content plateaued at ~ 200 nM; (b) the bisindole scaffold surpassed other heterocyclic ring systems in efficacy; (c) a polar interaction possibly involving Gln575 in the pocket could supplant less specific hydrophobic interactions; and (d) the benzoic acid ester moiety did not appear to form specific contacts with the pocket. The importance of this hydrophobic group to compound potency suggests a mechanism whereby it might interact with a tertiary component during fusion, such as membrane. A promising small molecule 10b with sub-μM activity was discovered with molecular weight < 500 da and reduced logP compared to earlier compounds. The work provides insight into requirements for small molecule inhibition of HIV-1 fusion. |
| Databáze: | OpenAIRE |
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