Design of potent anti-HIV molecules is still a great problem due to the ability of virus to the multiple mutations that cause the emerging resistance to the chemotherapy. Our work aimed to the joint use of QSAR and Fragment-Based Drug Design (FBDD) methods for finding new molecules with anti-HIV action. To create the QSAR models with GUSAR program (Filimonov et al., 2009; Zakharov et al., 2012), we used the data on structure and activity of known HIV inhibitors extracted from the Integrity database (Thomson Reuters). The data were divided onto different training sets depending on the target (reverse transcriptase, integrase, etc.), virus (wild or mutated form) and method used for the activity measurement. Array of the best QSAR models validated by leave-many-out procedure was applied for selecting of potential anti-HIV molecules among the commercially available and in silico generated libraries of compounds. To generate the structural formulae of potential anti-HIV agents, we used the in-house developed FBDD method (Filz et al., 2012). Two modes of generation were used: (1) consideration of all possible combinations of fragments based on the predefined rules; (2) transformations based on changes of chemical substituents, which are most likely to occur in a certain chemical scaffold. Several filers, which include estimating of physical and chemical properties and synthesability, were applied to reduce the number of selected molecules. Results of the selection were evaluated using the cross-search in publicly available databases of biologically active molecules (PubChem, NIAID, ChEMBL, a.o.). Newly found potential anti-HIV agents were recommended for purchase/synthesis and biological activity testing in anti-HIV assays.

Combining QSAR-analysis and fragment-based drug design in search for new anti-HIV agents

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.