Antibacterial activities, PASS prediction and ADME analysis of phytochemicals from Curcubita moschata, Curcubita maxima, and Irvingia gabonensis: insights from in silico studies.

Microbial infection management and treatment are crucial as a result of the prevalent antimicrobial resistance issue. Progressive studies are being carried out on how to develop drugs that can mitigate the resistance trends of these microorganisms. Secondary metabolites of plants can also be employed and accessed for this role, as the current study examines the antibacterial activities of phytochemicals from three (3) plants (Cucubita moschata, Cucubita maxima, and Irvingia gabonesis) through computational approaches. Molecular docking studies were carried out to show the binding affinities of the phytochemicals against two target receptors (DNA gyrase and Penicillin Binding Protein 3). In addition, drug likeness analysis, bioactivity and oral-bioavailability properties, absorption, distribution, metabolism, and excretion (ADME) profiling, as well as prediction of activity spectra for substances (PASS) using online tools like SwissADME, PASS online, AdmetSAR2, and Discovery Studio, were also performed. The results obtained identified isochlorogenic acid and apigenin-7-O-glucoside for DNA gyrase (1KZN) and apigenin-7-O-glucoside for Penicillin Binding Protein 3 (4BJP), which were further subjected to molecular dynamics simulation (MDS) and therefore recommended as the lead compounds.

Virtual screening, ADMET profiling, PASS prediction, and bioactivity studies of potential inhibitory roles of alkaloids, phytosterols, and flavonoids against COVID-19 main protease (Mpro).

The current research used a virtual screening method to study 57 isolated phytochemicals (alkaloids, phytosterols, and flavonoids) against the SARS-CoV-2 main protease (Mpro). The absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the selected compounds were analysed using admetSAR tool while SwissADME and Molinspiration chemoinformatics tools were used to examine the oral bioavailability and drug-likeness properties. Parameters such as physicochemical properties, activity spectra for substances (PASS) prediction, bioactivity, binding mode, and molecular interactions were also analysed. Our results favoured Lupeol (-8.6 kcal/mol), Lupenone (-7.7 kcal/mol), Hesperetin (-7.4 kcal/mol), Apigenin (-7.3 kcal/mol) and Castasterone (-7.3 kcal/mol) as probable inhibitors of SARS-CoV-2. This is because of their good binding affinities, bioactivities, drug-likeness, ADMET properties, PASS properties, oral bioavailability, binding mode and their interactions with the active site of the target receptor compared to Remdesivir and Azithromycin. Therefore, these compounds could be explored towards the development of new therapeutic agents against SARS-CoV-2.

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors - An insight into the atomistic mechanisms of their antioxidant potential.

Inhibitors of Keap1 would disrupt the covalent interaction between Keap1 and Nrf2 to unleash Nrf2 transcriptional machinery that orchestrates its cellular antioxidant, cytoprotective and detoxification processes thereby, protecting the cells against oxidative stress mediated diseases. In this in silico research, we investigated the Keap1 inhibiting potential of fifty (50) antioxidants using pharmacokinetic ADMET profiling, bioactivity assessment, physicochemical studies, molecular docking investigation, molecular dynamics and Quantum mechanical-based Density Functional Theory (DFT) studies using Keap1 as the apoprotein control. Out of these 50 antioxidants, Maslinic acid (MASA), 18-alpha-glycyrrhetinic acid (18-AGA) and resveratrol stand out by passing the RO5 (Lipinski rule of 5) for the physicochemical properties and ADMET studies. These three compounds also show high binding affinity of -10.6 kJ/mol, -10.4 kJ/mol and -7.8 kJ/mol at the kelch pocket of Keap1 respectively. Analysis of the 20ns trajectories using RMSD, RMSF, ROG and h-bond parameters revealed the stability of these compounds after comparing them with Keap1 apoprotein. Furthermore, the electron donating and accepting potentials of these compounds was used to investigate their reactivity using Density Functional Theory (HOMO and LUMO) and it was revealed that resveratrol had the highest stability based on its low energy gap. Our results predict that the three compounds are potential drug candidates with domiciled therapeutic functions against oxidative stress-mediated diseases. However, resveratrol stands out as the compound with the best stability and therefore, could be the best candidate with the best therapeutic efficacy.

Exploring the inhibitory potentials of Momordica charantia bioactive compounds against Keap1-Kelch protein using computational approaches.

The search for Keap1 inhibitors as potential Nrf2 activator is a way of increasing the antioxidant status of the human cellular environ. In this research, we used in silico methods to investigate Keap1-kelch inhibitory potential of Momordica charantia's bioactive compounds in order to predict their Nrf2 activating potential. ADMET profiling, physicochemical properties, molecular docking, molecular dynamics, and Molecular Mechanics-Poisson Boltzmann Surface Area (g_MMPBSA) free energy calculation studies were executed to drive home our aim. Out of all the bioactive compounds of Momordica charantia, catechin (CAT) and chlorogenic acid (CGA) were selected based on their ADMET profile, physicochemical properties, and molecular docking analysis. Molecular docking studies of CAT and CGA to Keap1 kelch domain showed that they have - 9.2 kJ/mol and - 9.1 kJ/mol binding energies respectively with CAT having four hydrogen bond interactions with Keap1 while CGA had three. Analysis after the 30 ns molecular dynamics simulation revealed that CAT and CGA were both stable, although with minimal conformational alterations at the kelch pocket of Keap1. Finally, MMPBSA calculation of the Gibbs free energy of each amino acid interaction with CAT and CGA revealed that CAT had a higher total binding energy than CGA. Therefore, the Keap1 inhibitory capacities and the molecular dynamic characters of CAT and CGA at the Kelch domain of Keap1 suggest a putative Nrf2 signaling activating prowess. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00100-2.

Target-based drug discovery, ADMET profiling and bioactivity studies of antibiotics as potential inhibitors of SARS-CoV-2 main protease (Mpro).

A recent outbreak of a new strain of Coronavirus (SARS-CoV-2) has become a global health burden, which has resulted in deaths. No proven drug has been found to effectively cure this fast-spreading infection, hence the need to explore old drugs with the known profile in tackling this pandemic. A computer-aided drug design approach involving virtual screening was used to obtain the binding scores and inhibiting efficiencies of previously known antibiotics against SARS-CoV-2 main protease (Mpro). The drug-likeness analysis of the repurposed drugs were done using the Molinspiration chemoinformatics tool, while the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis was carried out using ADMET SAR-2 webserver. Other analyses performed include bioactivities of the repurposed drug as a probable anti-SARS-CoV-2 agent and oral bioavailability analyses among others. The results were compared with those of drugs currently involved in clinical trials in the ongoing pandemic. Although antibiotics have been speculated to be of no use in the treatment of viral infections, literature has emerged lately to reveal the antiviral potential and immune-boosting ability of antibiotics. This study identified Tarivid and Ciprofloxacin with binding affinities of - 8.3 kcal/mol and - 8.1 kcal/mol, respectively as significant inhibitors of SARS-CoV-2 (Mpro) with better pharmacokinetics, drug-likeness and oral bioavailability, bioactivity properties, ADMET properties and inhibitory strength compared to Remdesivir (- 7.6 kcal/mol) and Azithromycin (- 6.3 kcal/mol). These observations will provide insight for further research (clinical trial) in the cure and management of COVID-19.

In silico investigation of saponins and tannins as potential inhibitors of SARS-CoV-2 main protease (Mpro).

It is no longer news that a novel strain of coronavirus named SARS-CoV-2 is ravaging the health sector worldwide, several attempts have been made to curtail this pandemic via repurposing of old drugs but at the present, available drugs are not adequately effective. Over the years, plant phytochemicals are increasingly becoming alternative sources of antimicrobial agents with novel mechanisms of action and limited side effects compared to synthetic drugs. Isolated saponins and tannins were evaluated for antiviral activity against SARS-CoV-2 (Mpro) via Molecular Docking and it was observed that a handsome number of the phytochemicals had binding affinities much better than Remdesivir, Dexamethasone, and N3 inhibitor which were used as the standards in this study. Further investigation of drug-likeness, ADMET profile, PASS profile, oral bioavailability, bioactivity, binding mode, and molecular interactions of these phytochemicals revealed that binding affinity alone is not enough to justify the potency of a molecule in the drug discovery process, as only 4 among the screened compounds passed all the analyses and are identified as potential inhibitors of SARS-CoV-2 (Mpro). This preliminary study thereby recommends Ellagic acid (- 8.4 kcal/mol), Arjunic Acid (- 8.1 kcal/mol), Theasapogenol B (- 8.1 kcal/mol), and Euscaphic Acid (- 8.0 kcal/mol) as potential inhibitors of SARS-CoV-2 (Mpro) with better pharmacokinetics and bioavailability compared to Remdesivir which is currently used compassionately.