Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Abstract

The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina’s capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of −8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (−46.97 to −118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

Molecular Docking and Dynamics Simulation Studies Predict Potential Anti-ADAR2 Inhibitors: Implications for the Treatment of Cancer, Neurological, Immunological and Infectious Diseases

“…The natural sources of the nine potential lead compounds were investigated from various databases, including ZINC15 [ 163 ], PubChem [ 164 , 165 ], ChEMBL [ 166 , 167 , 168 ], LOTUS [ 169 ], KNApSAcK [ 170 , 171 ], Natural Product Activity and Species Source (NPASS) [ 172 ], and Indian Medicinal Plants, Phytochemistry And Therapeutics (IMPPAT) [ 173 ] as previously conducted [ 174 ]. The pharmacological activities of the plant sources were also probed from the existing literature.…”

Computational Screening of Neuropilin‐1 Unveils Novel Potential Anti‐SARS‐CoV‐2 Therapeutics

“…Energy decomposition per residue is a measure of the energy each residue in a protein‐ligand complex contributes to ligand interaction with a receptor [84] . Residues that contribute energy less than −5 kJ/mol or greater than 5 kJ/mol have been reported to be critical residues in the ligand interaction with a receptor [85] . For the NRP‐1‐CNP0435132 complex, Asp320 contributed 5.8 kJ/mol, implying its crucial role in ligand binding to NRP‐1 (Figure S2).…”

“…[84] Residues that contribute energy less than À 5 kJ/mol or greater than 5 kJ/mol have been reported to be critical residues in the ligand interaction with a receptor. [85] For the NRP-1-CNP0435132 complex, Asp320 contributed 5.8 kJ/mol, implying its crucial role in ligand binding to NRP-1 (Figure S2). This corroborates earlier studies where Asp320 was reported as a critical residue in the ligand binding of NRP-1.…”

An In vitro and in silico investigation of the antitrypanosomal activities of the stem bark extracts of Anopyxis klaineana (Pierre) Engl

“…Previous studies have shown that AutoDock Vina can distinguish between active and non-active binders with an AUC of ROC curves ranging between 0.7 and 0.99. AutoDock Vina has also been shown to successfully predict the binding pose of ligands in the binding pocket of proteins [ 52 , [53] , [54] , [55] ].…”