Saponins are steroidal or triterpenoid glycoside that is distinguished by the soap-forming nature. Different saponins have been characterized and purified and are gaining attention in cancer chemotherapy. Saponins possess high structural diversity, which is linked to the anticancer activities. Several studies have reported the role of saponins in cancer and the mechanism of actions, including cell-cycle arrest, antioxidant activity, cellular invasion inhibition, induction of apoptosis and autophagy. Despite the extensive research and significant anticancer effects of saponins, there are currently no known FDA-approved saponin-based anticancer drugs. This can be attributed to a number of limitations, including toxicities and drug-likeness properties. Recent studies have explored options such as combination therapy and drug delivery systems to ensure increased efficacy and decreased toxicity in saponin. This review discusses the current knowledge on different saponins, their anticancer activity and mechanisms of action, as well as promising research within the last two decades and recommendations for future studies.
The inhibitory potential of Artemisia annua, a well-known antimalarial herb, against several viruses, including the coronavirus, is increasingly gaining recognition. The plant extract has shown significant activity against both the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the novel SARS-CoV-2 that is currently ravaging the world. It is therefore necessary to evaluate individual chemicals of the plant for inhibitory potential against SARS-CoV-2 for the purpose of designing drugs for the treatment of COVID-19. In this study, we employed computational techniques comprising molecular docking, binding free energy calculations, pharmacophore modeling, induced-fit docking, molecular dynamics simulation, and ADMET predictions to identify potential inhibitors of the SARS-CoV-2 main protease (Mpro) from 168 bioactive compounds of Artemisia annua. Rhamnocitrin, isokaempferide, kaempferol, quercimeritrin, apigenin, penduletin, isoquercitrin, astragalin, luteolin-7-glucoside, and isorhamnetin were ranked the highest, with docking scores ranging from −7.84 to −7.15 kcal/mol compared with the −6.59 kcal/mol demonstrated by the standard ligand. Rhamnocitrin, Isokaempferide, and kaempferol, like the standard ligand, interacted with important active site amino acid residues like HIS 41, CYS 145, ASN 142, and GLU 166, among others. Rhamnocitrin demonstrated good stability in the active site of the protein as there were no significant conformational changes during the simulation process. These compounds also possess acceptable druglike properties and a good safety profile. Hence, they could be considered for experimental studies and further development of drugs against COVID-19.
Owing to the urgent need for therapeutic intervention against the SARS-coronavirus 2 (SARS-CoV-2) pandemic, we employed an in silico approach to evaluate the SARS-CoV-2 inhibitory potential of newly synthesized imidazoles. The inhibitory potential of the compounds against SARS-CoV-2 drug targets - main protease (Mpro), spike protein (Spro) and RNA-dependent RNA polymerase (RdRp) were investigated through molecular docking analysis. The binding free energy of the protein-ligand complexes were estimated, pharmacophore models were generated and the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the compounds were determined. The compounds displayed various levels of binding affinities for the SARS-CoV-2 drug targets. Bisimidazole C2 scored highest against all the targets, with its aromatic rings including the two imidazole groups contributing to the binding. Among the phenyl-substituted 1H-imidazoles, C11 scored highest against all targets. C15 scored highest against Spro and C16 against Mpro and RdRp among the thiophene-imidazoles. The compounds interacted with HIS 41 - CYS 145 and GLU 288 – ASP 289 – GLU 290 of Mpro, ASN 501 of Spro receptor binding motif and some active site amino acids of RdRp. These novel imidazole compounds could be further developed as drug candidates against SARS-CoV-2 following lead optimization and experimental studies.
Alzheimer disease (AD) is the most common form of dementia contributing to about 60-70% of cases. β-Site amyloid precursor protein cleaving enzyme-1 (BACE1) plays an important role in the onset of AD and has become one of the important drug targets for AD. This approach has led to the development of promising BACE1 inhibitors, many of which are going through different phases of clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new drugs to uncover the mystery behind AD. This study focused on virtual screening of ~ 33,000 natural compounds to find potential BACE1 inhibitors. Multiple ligands pharmacophore model was generated using PHASE to screen retrieved compounds against a four-site (ADDR) hypothesis. Molecular docking was performed to predict the binding status of the natural compounds. Based on binding affinity, the top eight compounds were chosen for further analysis. The docked complexes were analyzed for binding free energy using PRIME MM/GBA calculation. The compounds were filtered for drug-likeness using ADME/TOX (absorption, distribution, metabolism, excretion and toxicity) prediction. AutoQSAR (automated quantitative structure activity relationship) was used to build a model for the prediction of compounds bioactivities. Despite retrieving a large number of compounds with favorable binding affinity, only a few were selected to be promising based on their ADME/TOX proprieties, binding free energy and predicted pIC 50. This study identified four natural compounds (NPC469686, NPC262328, NPC29763 and NPC86744) as novel BACE1 inhibitors. The insights obtained from this study could be employed to produce next-generation drug for AD.
SARS-CoV-2 is a new strain of Coronavirus that caused the pneumonia outbreak in Wuhan, China and has spread to over 200 countries of the world. It has received worldwide attention due to its virulence and high rate of infection. So far, several drugs have experimented against SARS-CoV-2, but the failure of these drugs to specifically interact with the viral protease necessitates urgent measure to boost up researches for the development of effective therapeutics against SARS-CoV-2. Papain-like protease (PLpro) of the viral polyproteins is essential for maturation and infectivity of the virus, making it one of the prime targets explored for SARS-CoV-2 drug design. This study was conducted to evaluate the efficacy of ~ 50,000 natural compounds retrieved from IBS database against COVID-19 PLpro using computer-aided drug design. Based on molecular dock scores, molecular interaction with active catalytic residues and molecular dynamics (MD) simulations studies, STOCK1N-69160 [(S)-2-((R)-4-((R)-2-amino-3-methylbutanamido)-3-(4-chlorophenyl) butanamido) propanoic acid hydrochloride] has been proposed as a novel inhibitor against COVID-19 PLpro. It demonstrated favourable docking score, the free energy of binding, interacted with key amino acid residues necessary for PLpro inhibition and also showed significant moderation for parameters investigated for ADME/tox (Adsorption, distribution, metabolism, excretion and toxicological) properties. The edge of the compound was further established by its stability in MD simulation conducted for 30 ns employing GROMACS software. We propose that STOCK1N-69160 is worth further investigation for preventing SARS-CoV-2. Graphic abstract
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