Anti-parasitic drug discovery against Babesia microti by natural compounds: an extensive computational drug design approach

Tick-borne Babesiosis is a parasitic infection caused by Babesia microti that can infect both animals and humans and may spread by tick, blood transfusions, and organ transplantation. The current therapeutic options for B. microti are limited, and drug resistance is a concern. This study proposes using computational drug design approaches to find and design an effective drug against B. microti. The study investigated the potentiality of nine natural compounds against the pathogenic human B. microti parasite and identified Vasicinone and Evodiamine as the most promising drugs. The ligand structures were optimized using density functional theory, molecular docking, molecular dynamics simulations, quantum mechanics such as HOMO–LUMO, drug-likeness and theoretical absorption, distribution, metabolism, excretion, and toxicity (ADMET), and pharmacokinetics characteristics performed. The results showed that Vasicinone (−8.6 kcal/mol and −7.8 kcal/mol) and Evodiamine (−8.7 kcal/mol and −8.5 kcal/mol) had the highest binding energy and anti-parasitic activity against B. microti lactate dehydrogenase and B. microti lactate dehydrogenase apo form. The strongest binding energy was reported by Vasicinone and Evodiamine; the compounds were evaluated through molecular dynamics simulation at 100 ns, and their stability when they form complexes with the targeted receptors was determined. Finally, the pkCSM web server is employed to predict the ADMET qualities of specific molecules, which can help prevent negative effects that arise from taking the treatment. The SwissADME web server is used to assess the Lipinski rule of five and drug-likeness properties including topological polar surface area and bioavailability. The Lipinski rule is used to estimate significant drug-likeness. The theoretical pharmacokinetics analysis and drug-likeness of the selected compounds are confirmed to be accepted by the Lipinski rule and have better ADMET features. Thus, to confirm their experimental value, these mentioned molecules should be suggested to carry out in wet lab, pre-clinical, and clinical levels

Development of a new drug candidate for the inhibition of Lassa virus glycoprotein and nucleoprotein by modification of evodiamine as promising therapeutic agents

The Lassa virus (LASV), an RNA virus prevalent in West and Central Africa, causes severe hemorrhagic fever with a high fatality rate. However, no FDA-approved treatments or vaccines exist. Two crucial proteins, LASV glycoprotein and nucleoprotein, play vital roles in pathogenesis and are potential therapeutic targets. As effective treatments for many emerging infections remain elusive, cutting-edge drug development approaches are essential, such as identifying molecular targets, screening lead molecules, and repurposing existing drugs. Bioinformatics and computational biology expedite drug discovery pipelines, using data science to identify targets, predict structures, and model interactions. These techniques also facilitate screening leads with optimal drug-like properties, reducing time, cost, and complexities associated with traditional drug development. Researchers have employed advanced computational drug design methods such as molecular docking, pharmacokinetics, drug-likeness, and molecular dynamics simulation to investigate evodiamine derivatives as potential LASV inhibitors. The results revealed remarkable binding affinities, with many outperforming standard compounds. Additionally, molecular active simulation data suggest stability when bound to target receptors. These promising findings indicate that evodiamine derivatives may offer superior pharmacokinetics and drug-likeness properties, serving as a valuable resource for professionals developing synthetic drugs to combat the Lassa virus

Development of a new drug candidate for the inhibition of Lassa virus glycoprotein and nucleoprotein by modification of evodiamine as promising therapeutic agents

The Lassa virus (LASV), an RNA virus prevalent in West and Central Africa, causes severe hemorrhagic fever with a high fatality rate. However, no FDA-approved treatments or vaccines exist. Two crucial proteins, LASV glycoprotein and nucleoprotein, play vital roles in pathogenesis and are potential therapeutic targets. As effective treatments for many emerging infections remain elusive, cutting-edge drug development approaches are essential, such as identifying molecular targets, screening lead molecules, and repurposing existing drugs. Bioinformatics and computational biology expedite drug discovery pipelines, using data science to identify targets, predict structures, and model interactions. These techniques also facilitate screening leads with optimal drug-like properties, reducing time, cost, and complexities associated with traditional drug development. Researchers have employed advanced computational drug design methods such as molecular docking, pharmacokinetics, drug-likeness, and molecular dynamics simulation to investigate evodiamine derivatives as potential LASV inhibitors. The results revealed remarkable binding affinities, with many outperforming standard compounds. Additionally, molecular active simulation data suggest stability when bound to target receptors. These promising findings indicate that evodiamine derivatives may offer superior pharmacokinetics and drug-likeness properties, serving as a valuable resource for professionals developing synthetic drugs to combat the Lassa virus.</p

Table_1_Novel computational and drug design strategies for inhibition of monkeypox virus and Babesia microti: molecular docking, molecular dynamic simulation and drug design approach by natural compounds.DOCX

BackgroundThe alarming increase in tick-borne pathogens such as human Babesia microti is an existential threat to global public health. It is a protozoan parasitic infection transmitted by numerous species of the genus Babesia. Second, monkeypox has recently emerged as a public health crisis, and the virus has spread around the world in the post-COVID-19 period with a very rapid transmission rate. These two novel pathogens are a new concern for human health globally and have become a significant obstacle to the development of modern medicine and the economy of the whole world. Currently, there are no approved drugs for the treatment of this disease. So, this research gap encourages us to find a potential inhibitor from a natural source.Methods and materialsIn this study, a series of natural plant-based biomolecules were subjected to in-depth computational investigation to find the most potent inhibitors targeting major pathogenic proteins responsible for the diseases caused by these two pathogens.ResultsAmong them, most of the selected natural compounds are predicted to bind tightly to the targeted proteins that are crucial for the replication of these novel pathogens. Moreover, all the molecules have outstanding ADMET properties such as high aqueous solubility, a higher human gastrointestinal absorption rate, and a lack of any carcinogenic or hepatotoxic effects; most of them followed Lipinski’s rule. Finally, the stability of the compounds was determined by molecular dynamics simulations (MDs) for 100 ns. During MDs, we observed that the mentioned compounds have exceptional stability against selected pathogens.ConclusionThese advanced computational strategies reported that 11 lead compounds, including dieckol and amentoflavone, exhibited high potency, excellent drug-like properties, and no toxicity. These compounds demonstrated strong binding affinities to the target enzymes, especially dieckol, which displayed superior stability during molecular dynamics simulations. The MM/PBSA method confirmed the favorable binding energies of amentoflavone and dieckol. However, further in vitro and in vivo studies are necessary to validate their efficacy. Our research highlights the role of Dieckol and Amentoflavone as promising candidates for inhibiting both monkeypox and Babesia microti, demonstrating their multifaceted roles in the control of these pathogens.</p

Table_2_Novel computational and drug design strategies for inhibition of monkeypox virus and Babesia microti: molecular docking, molecular dynamic simulation and drug design approach by natural compounds.DOCX

BackgroundThe alarming increase in tick-borne pathogens such as human Babesia microti is an existential threat to global public health. It is a protozoan parasitic infection transmitted by numerous species of the genus Babesia. Second, monkeypox has recently emerged as a public health crisis, and the virus has spread around the world in the post-COVID-19 period with a very rapid transmission rate. These two novel pathogens are a new concern for human health globally and have become a significant obstacle to the development of modern medicine and the economy of the whole world. Currently, there are no approved drugs for the treatment of this disease. So, this research gap encourages us to find a potential inhibitor from a natural source.Methods and materialsIn this study, a series of natural plant-based biomolecules were subjected to in-depth computational investigation to find the most potent inhibitors targeting major pathogenic proteins responsible for the diseases caused by these two pathogens.ResultsAmong them, most of the selected natural compounds are predicted to bind tightly to the targeted proteins that are crucial for the replication of these novel pathogens. Moreover, all the molecules have outstanding ADMET properties such as high aqueous solubility, a higher human gastrointestinal absorption rate, and a lack of any carcinogenic or hepatotoxic effects; most of them followed Lipinski’s rule. Finally, the stability of the compounds was determined by molecular dynamics simulations (MDs) for 100 ns. During MDs, we observed that the mentioned compounds have exceptional stability against selected pathogens.ConclusionThese advanced computational strategies reported that 11 lead compounds, including dieckol and amentoflavone, exhibited high potency, excellent drug-like properties, and no toxicity. These compounds demonstrated strong binding affinities to the target enzymes, especially dieckol, which displayed superior stability during molecular dynamics simulations. The MM/PBSA method confirmed the favorable binding energies of amentoflavone and dieckol. However, further in vitro and in vivo studies are necessary to validate their efficacy. Our research highlights the role of Dieckol and Amentoflavone as promising candidates for inhibiting both monkeypox and Babesia microti, demonstrating their multifaceted roles in the control of these pathogens.</p

Development of a new drug candidate for the inhibition of Lassa virus glycoprotein and nucleoprotein by modification of evodiamine as promising therapeutic agents

The Lassa virus (LASV), an RNA virus prevalent in West and Central Africa, causes severe hemorrhagic fever with a high fatality rate. However, no FDA-approved treatments or vaccines exist. Two crucial proteins, LASV glycoprotein and nucleoprotein, play vital roles in pathogenesis and are potential therapeutic targets. As effective treatments for many emerging infections remain elusive, cutting-edge drug development approaches are essential, such as identifying molecular targets, screening lead molecules, and repurposing existing drugs. Bioinformatics and computational biology expedite drug discovery pipelines, using data science to identify targets, predict structures, and model interactions. These techniques also facilitate screening leads with optimal drug-like properties, reducing time, cost, and complexities associated with traditional drug development. Researchers have employed advanced computational drug design methods such as molecular docking, pharmacokinetics, drug-likeness, and molecular dynamics simulation to investigate evodiamine derivatives as potential LASV inhibitors. The results revealed remarkable binding affinities, with many outperforming standard compounds. Additionally, molecular active simulation data suggest stability when bound to target receptors. These promising findings indicate that evodiamine derivatives may offer superior pharmacokinetics and drug-likeness properties, serving as a valuable resource for professionals developing synthetic drugs to combat the Lassa virus. </p