Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Abstract

Background: Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS2B/NS3 protease complex is a target for designing specific antivirals due to its importance in viral replication and its high degree of conservation.Methods: NS2B/NS3 protease complex structural information was employed to find small molecules that are capable of inhibiting the activity of the enzyme complex. This inhibitory activity was probed with in vitro assays using a fluorescent substrate and the complex NS2B/NS3 obtained by recombinant DNA techniques, for testing the activity against dengue virus replication, HepG2 cells infected with dengue virus serotype 2 were used. Results: A total of 210,903 small molecules from PubChem were docked in silico to the NS2B/NS3 structure (PDB: 2FOM) to find molecules that were capable of inhibiting this protein complex. Five of the best 500 leading compounds, according to their affinity values (-11.6 and -13.5 kcal/mol), were purchased. The inhibitory protease activity on the recombinant protein and antiviral assays was tested. Conclusions: Chemicals CID54681617, CID54692801 and CID54715399 were strong inhibitors of NS2B/NS3, with IC 50 values (µM) and percentages of viral titer reductions of 19.9, 79.9%; 17.5, 69.8%; and 9.1, 73.9 %, respectively. Multivariate methods applied to the molecular descriptors showed two compounds that were structurally different from other DENV inhibitors. General significance: This discovery opens new possibilities for obtaining drug candidates against Dengue virus.

Thioguanine-based DENV-2 NS2B/NS3 protease inhibitors: Virtual screening, synthesis, biological evaluation and molecular modelling

“…Nevertheless, many peptidic or modified peptidic molecules have been discovered to have good NS2B/NS3pro inhibition activities [15,[24][25][26][27][28][29][30]. In addition, there are also reports of potent small molecule NS2B/ NS3pro inhibitors from natural products (panduratin [31], agathisflavone and quercetin [32]), from synthetic medicinal chemistry (dehydronaphthalene [33], benzimidazole [34], and thiadiazoloacrylamide [35]) or from the utilisation of computational methods [36][37][38][39].…”

Natural Products as Chemopreventive Agents by Potential Inhibition of the Kinase Domain in ErbB Receptors

“…During the developmental stages of more effective medication candidates, it is likely to have various unsuccessful attempts at reaching a promissory compound for further study and clinical trials, on account of pharmacokinetic limitations, undesirable toxicities, and instabilities, properties that can be detected by using specialized programs, such as FAF-Drugs3 [ 42 ]. This server is able to predict ADME/Tox properties, such as absorption, distribution, metabolism, excretion and toxicity, as well as descriptors to ultimately reduce time, resources and costs on apparent promising candidates.…”

Target Identification Using Homopharma and Network-Based Methods for Predicting Compounds Against Dengue Virus-Infected Cells

“…Therefore, not only viral proteins but also human factors could also be interrupted by these active compounds, raising the possibility of adverse side effects. Although many studies have revealed the ability of potent compounds that could interrupt several proteins and host factors in human cells [7,14,15,[24][25][26], one of the challenging quests is to search for the probable protein targets of active compounds, which is an arduous step for drug discovery and design [27][28][29][30][31]. Once discovered, the potent molecules can be further optimized to increase their efficiency using the information on the interaction between the compound and key residues in the target binding site.…”