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Dengue fever is a mosquito-borne viral disease that has become a major public health concern worldwide. This disease presents with a wide range of clinical manifestations, from a mild cold-like illness to the more serious hemorrhagic dengue fever and dengue shock syndrome. Currently, neither an approved drug nor an effective vaccine for the treatment are available to fight the disease. The envelope protein (E) is a major component of the virion surface. This protein plays a key role during the viral entry process, constituting an attractive target for the development of antiviral drugs. The crystal structure of the E protein reveals the existence of a hydrophobic pocket occupied by the detergent n- octyl-β-d-glucoside (β-OG). This pocket lies at the hinge region between domains I and II and is important for the low pH-triggered conformational rearrangement required for the fusion of the virion with the host's cell. Aiming at the design of novel molecules which bind to E and act as virus entry inhibitors, we undertook a de novo design approach by "growing" molecules inside the hydrophobic site (β-OG). From more than 240000 small-molecules generated, the 2,4 pyrimidine scaffold was selected as the best candidate, from which one synthesized compound displayed micromolar activity. Molecular dynamics-based optimization was performed on this hit, and thirty derivatives were designed in silico, synthesized and evaluated on their capacity to inhibit dengue virus entry into the host cell. Four compounds were found to be potent antiviral compounds in the low-micromolar range. The assessment of drug-like physicochemical and in vitro pharmacokinetic properties revealed that compounds 3e and 3h presented acceptable solubility values and were stable in mouse plasma, simulated gastric fluid, simulated intestinal fluid, and phosphate buffered saline solution. Image 1 • De novo design approach was used to identify new compounds against DENV E protein. • Lead Optimization was performed via molecular dynamics. • Several compounds displayed excellent potency against DENV. • Compounds 3e and 3h were potent compounds of all four sero-types of DENV. • 3e and 3h showed acceptable in vitro pharmacokinetics profile. [ABSTRACT FROM AUTHOR]

Bovine viral diarrhea virus (BVDV) is known to cause financial losses and decreased productivity in the cattle industry worldwide. Currently, there are no available antiviral treatments for effectively controlling BVDV infections in laboratories or farms. The BVDV envelope protein (E2) mediates receptor recognition on the cell surface and is required for fusion of virus and cell membranes after the endocytic uptake of the virus during the entry process. Therefore, E2 is an attractive target for the development of antiviral strategies. To identify BVDV antivirals targeting E2 function, we defined a binding site in silico located in domain IIIc at the interface between monomers in the disulfide linked dimer of E2. Employing a de novo design methodology to identify compounds with the potential to inhibit the E2 function, compound 9 emerged as a promising candidate with remarkable antiviral activity and minimal toxicity. In line with targeting of E2 function, compound 9 was found to block the virus entry into host cells. Furthermore, we demonstrated that compound 9 selectively binds to recombinant E2 in vitro. Molecular dynamics simulations (MD) allowed describing a possible interaction pattern between compound 9 and E2 and indicated that the S enantiomer of compound 9 may be responsible for the antiviral activity. Future research endeavors will focus on synthesizing enantiomerically pure compounds to further support these findings. These results highlight the usefulness of de novo design strategies to identify a novel class of BVDV inhibitors that block E2 function inhibiting virus entry into the host cell. • BVDV envelope protein E2 was selected as a target for novel antiviral development. • De novo design identified tetrahydroquinoline derivative compound 9 as potent E2 inhibitor. • Compound 9 blocked virus entry into host cells. • In vitro binding of compound 9 to recombinant E2 validated its target specificity. [ABSTRACT FROM AUTHOR]

The development of open computational pipelines to accelerate the discovery of treatments for emerging diseases allows finding novel solutions in shorter periods of time. Consensus molecular docking is one of these approaches, and its main purpose is to increase the detection of real actives within virtual screening campaigns. Here we present dockECR, an open consensus docking and ranking protocol that implements the exponential consensus ranking method to prioritize molecular candidates. The protocol uses four open source molecular docking programs: AutoDock Vina, Smina, LeDock and rDock, to rank the molecules. In addition, we introduce a scoring strategy based on the average RMSD obtained from comparing the best poses from each single program to complement the consensus ranking with information about the predicted poses. The protocol was benchmarked using 15 relevant protein targets with known actives and decoys, and applied using the main protease of the SARS-CoV-2 virus. For the application, different crystal structures of the protease, and frames obtained from molecular dynamics simulations were used to dock a library of 79 molecules derived from previously co-crystallized fragments. The ranking obtained with dockECR was used to prioritize eight candidates, which were evaluated in terms of the interactions generated with key residues from the protease. The protocol can be implemented in any virtual screening campaign involving proteins as molecular targets. The dockECR code is publicly available at: https://github.com/rochoa85/dockECR. [Display omitted] ∙ The open consensus docking and ranking protocol called dockECR is able to rank molecules based on predicted scores and pose conservation. ∙A benchmark analysis with 15 targets reporting actives and decoys was performed to validate the protocol. ∙The method was implemented to select eight potential molecular binders of SARS-CoV-2 main protease (MPro). ∙The chemical structures are provided together with information of key interactions within the protein binding site. ∙The open dockECR code is provided to reproduce the results and apply it with other protein targets of interest. [ABSTRACT FROM AUTHOR]