Estudos de modelagem molecular, de homologia e ancoramento de proteínas dead-box ddx3 para fins de desenvolvimento de compostos antivirais

Abstract

The emergence of multiple drug-resistant strains poses a risk of failure in antiviral therapy. As a result of this condition, there is a need to identify new drugs that can be used against these pathogens in the development of safe and effective therapeutic agents. Recent studies suggest that cellular cofactors are involved in important steps of viral replication. The DEAD-box RNA helicase DDX3 is a human enzyme that interacts with proteins encoded by some viruses, and that use it to favor their replication. In the present work, we carried out studies of protein homology modeling and molecular anchoring, toxicity and bioactivity prediction of antiviral candidate compounds. Since the three-dimensional structure of human DDX3 in its closed conformation is not experimentally available, DDX3 was predicted by homology modeling using the MODELLER 9v20 tool, using multiple models. The energy minimization of the modeled protein was done using Chimera 1.10.1 software and validated by the Ramachandran plot with 99.7% of DDX3 residues in the allowed region, and the overall quality factor was 78,247 using the ERRAT software which resulted in data validated for their stereochemical qualities. The protein model was used to anchor the compounds tidiazuron and ketoprofen potential inhibitors of DDX3 using Autodock 4.2 software. Interestingly, among the binding residues of both compounds are PHE 357 and THR 323. These residues play a fundamental role in the activity of DEAD-BOX DDX3 inhibitors. Thus, this study provides more information about the DDX3 helicase inhibitory relationships and opens the way for the design of effective strategies to overcome antiviral resistance by inhibiting the replication of viruses that use cellular cofactors. In addition, bioactivity profiles such as the “druglikeness”, “drugscore” and physicochemical properties filter of Lipinski's rule of five, of these compounds resulted in promising values and, therefore, these potential inhibitory agents can be taken in pre-clinical studies. -clinical and clinical as antiviral therapy.