Computational discovery of dual potential inhibitors of SARS-CoV-2 spike/ACE2 and Mpro: 3D-pharmacophore, docking-based virtual screening, quantum mechanics and molecular dynamics.

To find drugs against COVID-19, caused by the SARS-CoV-2, promising targets include the fusion of the viral spike with the human angiotensin-converting enzyme 2 (ACE2) as well as the main protease (Mpro). These proteins are responsible for viral entry and replication, respectively. We combined several state-of-the-art computational methods, including, protein-ligand interaction fingerprint, 3D-pharmacophores, molecular-docking, MM-GBSA, DFT, and MD simulations to explore two databases: ChEMBL and NANPDB to identify molecules that could both block spike/ACE2 fusion and inhibit Mpro. A total of 1,690,649 compounds from the two databases were screened using the pharmacophore model obtained from PLIF analysis. Five recent complexes of Mpro co-crystallized with different ligands were used to generate the pharmacophore model, allowing 4,829 compounds that passed this prefilter. These were then submitted to molecular docking against Mpro. The 5% top-ranked docking hits from docking result having scores < -8.32 kcal mol-1 were selected and then docked against spike/ACE2. Only four compounds: ChEMBL244958, ChEMBL266531, ChEMBL3680003, and 1-methoxy-3-indolymethyl glucosinolate (4) displayed binding energies < - 8.21 kcal mol-1 (for the native ligand) were considered as putative dual-target inhibitors. Furthermore, predictive ADMET, MM-GBSA and DFT/6-311G(d,p) were performed on these compounds and compared with those of well-known antivirals. DFT calculations showed that ChEMBL244958 and compound 4 had significant predicted reactivity values. Molecular dynamics simulations of the docked complexes were run for 100 ns and used to validate the stability docked poses and to confirm that these hits are putative dual binders of the spike/ACE2 and the Mpro.

The potential of anti-malarial compounds derived from African medicinal plants: a review of pharmacological evaluations from 2013 to 2019.

BACKGROUND: African Traditional Medicine (ATM) is used for the healthcare of about 80% of the rural populations of the continent of Africa. The practices of ATM make use of plant-products, which are known to contain plant-based secondary metabolites or natural products (NPs), likely to play key roles in drug discovery, particularly as lead compounds. For various reasons, including resistance of strains of Plasmodium to known anti-malarial drugs, local African populations often resort to plant-based treatments and/or a combination of this and standard anti-malarial regimens. Emphasis has been laid in this review to present the anti-malarial virtue of the most recently published phytochemicals or natural products, which have been tested by in vitro and in vivo assays. METHODS: The data was based on the current version of the African Compound Libraries, which are constantly being updated based on inputs from journal articles and student theses (M.Sc/Ph.D) from African University libraries. Emphasis was laid on data published after 2012. In order to carry out the original data collection, currently being included in the African Compounds Database, individual journal websites were queried using the country names in Africa as search terms. Over 40,000 articles "hits" were originally retrieved, then reduced to about 9000 articles. The retained articles/theses was further queried with the search terms "malaria", "malarial", "plasmodium", "plasmodial" and a combination of them, resulting in over 500 articles. Those including compounds with anti-malarial activities for which the measured activities fell within the established cut off values numbered 55, which were all cited in the review as relevant references. RESULTS AND DISCUSSION: Pure compounds derived from African medicinal plants with demonstrated anti-malarial/antiplasmodial properties with activities ranging from "very active" to "weakly active" have been discussed. The majority of the 187 natural products were terpenoids (30%), followed by flavonoids (22%), alkaloids (19%) and quinones (15%), with each of the other compound classes being less than 5% of the entire compound collection. It was also observed that most of the plant species from which the compounds were identified were of the families Rubiaceae, Meliaceae and Asphodelaceae. The review is intended to continue laying the groundwork for an African-based anti-malarial drug discovery project.