Recently emerged SARS-CoV-2 caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear, threatening global health safety. To date, no licensed antiviral drugs or vaccines are available against COVID-19 although several clinical trials are under way to test possible therapies. During this urgent situation, computational drug discovery methods provide an alternative to tiresome high-throughput screening, particularly in the hit-to-lead-optimization stage. Identification of small molecules that specifically target viral replication apparatus has indicated the highest potential towards antiviral drug discovery. In this work, we present potential compounds that specifically target SARS-CoV-2 vital proteins, including the main protease, Nsp12 RNA polymerase and Nsp13 helicase. An integrative virtual screening and molecular dynamics simulations approach has facilitated the identification of potential binding modes and favourable molecular interaction profile of corresponding compounds. Moreover, the identification of structurally important binding site residues in conserved motifs located inside the active site highlights relative importance of ligand binding based on residual energy decomposition analysis. Although the current study lacks experimental validation, the structural information obtained from this computational study has paved way for the design of targeted inhibitors to combat COVID-19 outbreak.

The present study explored phytochemicals, porcine pancreatic α-amylase (PPA) and lipase (PPL) inhibitory activities and antioxidant potential of polar and nonpolar extracts of the leaves and flowers of Ocimum basilicum and the in-silico mode of interaction between these enzymes and the major chemical constituents of the herb. The hexane extract (HE) and hydro-ethanolic extract (EE) obtained sequentially were used to estimate PPA and PPL inhibitory and antioxidant activities, total phenolic content (TPC) and total flavonoid content (TFC). Chemical constituents of the essential oils and HE were determined by GC-MS (Gas Chromatography-Mass Spectrometry). For PPA inhibition, IC₅₀ (µg/mL) of the extracts were 0.27–0.37, which were close to 0.24 of acarbose, while for PPL inhibition, IC₅₀ (µg/mL) of the extracts were 278.40–399.65, and that of Orlistat 145.72. The flowers EE was most potent antioxidant followed by leaves EE. The leaves EE had highest TPC and TFC followed of flowers EE. The essential oil of flowers had higher estragole (55%) than linalool (37%), while the essential oil of the leaves had higher linalool (42%) than estragole (38%). The HE of the flowers contained higher estragole (42%) than linalool (23%), while of the HE of the leaves too had higher estragole (65%) than linalool (18%). The in-silico molecular docking study showed linalool and estragole to have considerable PPA and PPL binding potential, which were further investigated through molecular dynamics simulations and binding free energy calculations. The PPA and PPL inhibitory activities of O. basilicum extracts and their notable antioxidant potential propose the herb as a multi-target complimentary medicine for diabetes, obesity and oxidative stress.

Cisplatin is amongst the most potent chemotherapeutic drugs with applications in more than 50% of cancer treatments, but dose-dependent side effects limit its usefulness. Berberis vulgaris L. (B. vulgaris) has a proven role in several therapeutic applications in the traditional medicinal system. High-performance liquid chromatography was used to quantify berberine, a potent alkaloid in the methanolic root extract of B. vulgaris (BvRE). Berberine chloride in BvRE was found to be 10.29% w/w. To assess the prophylactic and curative protective effects of BvRE on cisplatin-induced nephrotoxicity, hepatotoxicity, and hyperlipidemia, in vivo toxicity trials were carried out on 25 healthy male albino Wistar rats (130–180 g). Both prophylactic and curative trials included a single dose of cisplatin (4 mg/kg, i.p.) and nine doses of BvRE (500 mg/kg/day, orally). An array of marked toxicity effects appeared in response to cisplatin dosage evident by morphological condition, biochemical analysis of serum (urea, creatinine, total protein, alanine transaminase, aspartate transaminase, total cholesterol, and triglyceride), and organ tissue homogenates (malondialdehyde and catalase). Statistically-significant (p < 0.05) variations were observed in various parameters. Moreover, histological studies of liver and kidney tissues revealed that the protective effect of BvRE effectively minimized and reversed nephrotoxic, hepatotoxic, and hyperlipidemic effects caused by cisplatin in both prophylactic and curative groups with relatively promising ameliorative effects in the prophylactic regimen. The in vitro cell viability effect of cisplatin, BvRE, and their combination was determined on HeLa cells using the tetrazolium (MTT) assay. MTT clearly corroborated that HeLa cells appeared to be less sensitive to cisplatin and berberine individually, while the combination of both at the same concentrations resulted in growth inhibition of HeLa cells in a remarkable synergistic way. The present study validated the use of BvRE as a protective agent in combination therapy with cisplatin.

The Crimean-Congo Hemorrhagic Fever virus (CCHFV) is a segmented negative single-stranded RNA virus (−ssRNA) which causes severe hemorrhagic fever in humans with a mortality rate of ~50%. To date, no vaccine has been approved. Treatment is limited to supportive care with few investigational drugs in practice. Previous studies have identified viral RNA dependent RNA Polymerase (RdRp) as a potential drug target due to its significant role in viral replication and transcription. Since no crystal structure is available yet, we report the structural elucidation of CCHFV-RdRp by in-depth homology modeling. Even with low sequence identity, the generated model suggests a similar overall structure as previously reported RdRps. More specifically, the model suggests the presence of structural/functional conserved RdRp motifs for polymerase function, the configuration of uniform spatial arrangement of core RdRp sub-domains, and predicted positively charged entry/exit tunnels, as seen in sNSV polymerases. Extensive pharmacophore modeling based on per-residue energy contribution with investigational drugs allowed the concise mapping of pharmacophoric features and identified potential hits. The combination of pharmacophoric features with interaction energy analysis revealed functionally important residues in the conserved motifs together with in silico predicted common inhibitory binding modes with highly potent reference compounds.