Ebola still remains as one of the most problematic infectious diseases in Africa with a high rate of mortality. Although this disease has been known for an almost half-century, there are no vaccines and drugs available in the market to treat Ebola. Zaire ebolavirus (EBOV), a single-stranded RNA virus which belongs to Filoviridae family and Mononegavirales order, is one of the virus causing Ebola. As one of seven proteins that EBOV encodes, Ebola virus nucleoprotein (EBOV NP) plays an imperative role in EBOV proliferation cycle. Therefore, the development of a new Ebola treatment can be targeted towards EBOV NP. In this work, we screened about 190,084 natural product compounds from ZINC15 database through in silico virtual screening and flexible docking simulation. Furthermore, the bioavailability and toxicity prediction have been conducted as well. Two best ligands according to the simulation and prediction tests were progressed into the molecular dynamics simulation. In the end, we found that our proposed ligands, namely α-lipomycin (ZINC56874155) and 3-(((S)-1-amino-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-5-((5-((5R,7S)-5,7-dihydroxy-3-oxodecyl)-2-hydroxyphenoxy) methyl)pyrrolo[3,4-b]pyrrol-5-ium (ZINC85628951), showed the promising results to be developed as a lead compounds for treating Ebola. Therefore, an experimental study is required to validate their inhibition activities against EBOV NP.

Epimutation by DNA Methyltransferase 1 (DNMT1), an epigenetic regulator enzyme, may lead to the proliferation of breast cancer. In this report, 168,686 natural products from the PubChem database were screened and modified by in silico method to acquire the potential inhibitor of DNMT1. The initial screening of PubChem natural products using Lipinski’s and Veber’s rules of three and toxic properties have resulted in 2601 fragment candidates. Four fragments from pharmacophore-based molecular docking simulation were modified by utilizing FragFP and the Lipinski’s and Veber’s rules of five, and resulted in 51,200 ligands. The toxicological screening collected 13,563 ligands for a series of pharmacophore-based molecular docking simulations to sort out the modified ligands, which had the better binding activity and interactions to DNMT1 compared to the standards, SAH, SAM, and SFG. This step resulted in five ligand candidates, namely C-7756, C-5769, C-1723, C-2129, and C-2140. The ADME-Tox properties prediction showed that the selected ligands are generally better than standards in terms of druglikeness, GI absorption, and oral bioavailability. C-7756 exhibited a stronger affinity to DNMT1 as well as better ADME-Tox properties compared to the other ligands.

Dengue virus (DENV) has emerged as one of the most prevalent viruses in sub-tropical countries, yet there is no commercial drug available to combat DENV infection effectively. The RNA-capping and replication processes of DENV are regulated by NS5 methyltransferase (MTase). Hence, NS5 MTase is believed as a promising drug target for DENV. In this research, the DENV NS5 MTase was subjected to 6,842 Northern African Natural Product Database (NANPDB) compounds through computational simulation methods. Three crystal structures of DENV NS5 MTase, which contained S-adenosylhomocysteine (PDB ID: 4V0Q), S-adenosylmethionine (PDB ID: 3P97), and sinefungin (PDB ID: 4R8S), were used as the core template of the pharmacophore mapping in the SAH-binding site of DENV NS5 MTase. Four amino acid residues (Glu111, Asp131, Val132, and Asp146) were found to strongly interacted with SAH, SAM, and SFG, indicating that these residues may hold a vital role on the catalytic activity of DENV NS5 MTase. From the docking simulations, three ligands showed favorable inhibition activities by having lower ΔGbinding value than the standard ligands. Rutin has the lowest ΔGbinding value at -12.3586 kcal/mol, followed by isorhamnetin 3-rutinoside (-12.3203 kcal/mol), and tetra-o-galloyl glucose (-12.2039 kcal/mol). Pharmacological properties of these ligands were analyzed; no potential harmful effect was detected. Therefore, these ligands can be suggested as drug candidates for treating DENV infection by targeting SAH-binding site of NS5 MTase. The ligands efficacy needs to be validated through a series of in vitro, in vivo and clinical studies.