scholarly journals Fragment-Based Virtual Screening to Discover Potential Plasmodium PI4KIIIβ Ligands

2021 ◽  
Author(s):  
Akachukwu Ibezim ◽  
Mbanefo S. Madukaife ◽  
Sochi C Osigwe ◽  
Nadja Engel ◽  
Ramanathan Karuppasamy ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Plasmodium Species ◽  
Homology Model ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Active Site Residues ◽  
Starting Point ◽  
Binding Cavity

Plasmodium species that cause malaria, a disease responsible for about half a million deaths per annum despite concerted efforts to combat it. The causative agent depends on type III beta phosphatidylinositol 4-kinase (PPI4K) during the development of merozoite. PPI4K is the only clinically validated Plasmodium kinase so far and its inhibitors are effective both in vitro and in vivo. In this work, a small library of ~22 000 fragments was virtually screened using PPI4K homology model to discover potential ligands of the enzyme. 16 virtual hits were selected based on ≤ -9.0 kcal/mol binding energy cut off and were subjected to similarity and substructure searching after they had passed PAINS screening. The derivatives obtained showed improved binding energies, which ranged from -10.00 to -13.80 kcal/mol. Moreover, the topmost ranking compound 31, with interesting drug-like quality was stable within the protein’s binding cavity during the 10 ns molecular dynamics simulation period. In addition, analysis of its binding pose revealed some unique binding interactions with PPI4K active site residues as the basis for the observed improved binding affinity. Overall, compound 31 appears to be a viable starting point for the development of PPI4K inhibitors with antimalarial activity.

scholarly journals Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Ghazala Muteeb ◽  
Adil Alshoaibi ◽  
Mohammad Aatif ◽  
Md. Tabish Rehman ◽  
M. Zuhaib Qayyum
Keyword(s):  
Hydrophobic Interactions ◽  
In Silico Analysis ◽  
Salt Bridge ◽  
Competitive Inhibitor ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Energy Calculation

AbstractThe recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score <  − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

scholarly journals In VitroandIn VivoActivity of Solithromycin (CEM-101) against Plasmodium Species

2011 ◽  
Vol 56 (2) ◽  
pp. 703-707 ◽  
Author(s):  
Sergio Wittlin ◽  
Eric Ekland ◽  
J Carl Craft ◽  
Julie Lotharius ◽  
Ian Bathurst ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Antimalarial Activity ◽  
Plasmodium Species ◽  
Parasite Clearance ◽  
Response To Treatment ◽  
Cross Resistance ◽  
Asexual Blood Stage ◽  
Content Type

ABSTRACTWith the emergence ofPlasmodium falciparuminfections exhibiting increased parasite clearance times in response to treatment with artemisinin-based combination therapies, the need for new therapeutic agents is urgent. Solithromycin, a potent new fluoroketolide currently in development, has been shown to be an effective, broad-spectrum antimicrobial agent. Malarial parasites possess an unusual organelle, termed the apicoplast, which carries a cryptic genome of prokaryotic origin that encodes its own translation and transcription machinery. Given the similarity of apicoplast and bacterial ribosomes, we have examined solithromycin for antimalarial activity. Other antibiotics known to target the apicoplast, such as the macrolide azithromycin, demonstrate a delayed-death effect, whereby treated asexual blood-stage parasites die in the second generation of drug exposure. Solithromycin demonstrated potentin vitroactivity against the NF54 strain ofP. falciparum, as well as against two multidrug-resistant strains, Dd2 and 7G8. The dramatic increase in potency observed after two generations of exposure suggests that it targets the apicoplast. Solithromycin also retained potency against azithromycin-resistant parasites derived from Dd2 and 7G8, although these lines did demonstrate a degree of cross-resistance. In anin vivomodel ofP. bergheiinfection in mice, solithromycin demonstrated a 100% cure rate when administered as a dosage regimen of four doses of 100 mg/kg of body weight, the same dose required for artesunate or chloroquine to achieve 100% cure rates in this rodent malaria model. These promisingin vitroandin vivodata support further investigations into the development of solithromycin as an antimalarial agent.

scholarly journals Phloroglucinol as a Potential Candidate against Trypanosoma congolense Infection: Insights from In Vivo, In Vitro, Molecular Docking and Molecular Dynamic Simulation Analyses

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 469
Author(s):  
Nasirudeen Idowu Abdulrashid ◽  
Suleiman Aminu ◽  
Rahma Muhammad Adamu ◽  
Nasir Tajuddeen ◽  
Murtala Bindawa Isah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Studies ◽  
Binding Energies ◽  
Sub Saharan Africa ◽  
Dynamics Simulation ◽  
Potential Candidate ◽  
Inhibitory Effects ◽  
Hydrogen Bond Interaction

Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on T. congolense infection and its inhibitory effects on the partially purified T. congolense sialidase and phospholipase A2 (PLA2) were investigated. Treatment with phloroglucinol for 14 days significantly (p < 0.05) suppressed T. congolense proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against T. congolense-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream T. congolense sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA2 (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of −4.9 and −5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA2 respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (−67.84 ± 0.50 kJ/mol) than PLA2-phloroglucinol complex (−77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA2-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA2.

scholarly journals Dual targeting of cytokine storm and viral replication in COVID-19 by plant-derived steroidal pregnanes in silico

2021 ◽  
Author(s):  
Gideon A. Gyebi ◽  
Oludare M. Ogunyemi ◽  
Ibrahim M. Ibrahim ◽  
Saheed O. Afolabi ◽  
Joseph O. Adebayo
Keyword(s):  
In Silico ◽  
Glucocorticoid Receptors ◽  
Active Regions ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Mode Analysis ◽  
High Morbidity ◽  
Cytokine Storm

Abstract The high morbidity and mortality rate of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection arises majorly from the Acute Respiratory Distress Syndrome and “cytokine storm” syndrome, which is sustained by an aberrant systemic inflammatory response and elevated pro-inflammatory cytokines. Thus, phytocompounds with broad-spectrum anti-inflammatory activity that target multiple SARS-CoV-2 proteins will enhance the development of effective drugs against the disease. In this study, an in-house library of 106 steriodal plant-derived pregnanes (PDPs) was docked in the active regions of human glucocorticoid receptors (hGRs) in a comparative molecular docking analysis. Based on the minimal binding energy and a comparative dexamethason binding mode analysis, a list of top twenty ranked PDPs docked in the agonist conformation of hGR, with binding energies ranging between -9.8 and -11.2 Kcal/mol, was obtained and analyzed for interactions with the human Janus kinases 1 and Interleukins-6 and SARS-CoV-2 3-chymotrypsin-like protease, Papain-like protease and RNA-dependent RNA polymerase. For each target protein, the top three ranked PDPs were selected. Eight PDPs (bregenin, hirundigenin, anhydroholantogenin, atratogenin A, atratogenin B, glaucogenin A, glaucogenin C and glaucogenin D) with high binding tendencies to the catalytic residues of multiple targets were identified. A high degree of structural stability was observed from the 100 ns molecular dynamics simulation analyses of glaucogenin C and hirundigenin complexes of hGR. The selected top-eight ranked PDPs demonstrated favourable druggable and in silico ADMET properties. Thus, the therapeutic potentials of glaucogenin C and hirundigenin can be explored for further in vitro and in vivo studies.

scholarly journals Molecular docking and molecular dynamics simulation study of inositol phosphorylceramide synthase – inhibitor complex in leishmaniasis: Insight into the structure based drug design

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1610 ◽  
Author(s):  
Vineetha Mandlik ◽  
Shailza Singh
Keyword(s):  
Molecular Dynamics ◽  
Dynamics Simulation ◽  
Sphingolipid Metabolism ◽  
Drug Candidate ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Starting Point ◽  
Synthase Inhibitor

Inositol phosphorylceramide synthase (IPCS) has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis. Five coumarin derivatives were developed as inhibitors of IPCS protein. Molecular dynamics simulations of the complexes of IPCS with these inhibitors were performed which provided insights into the binding modes of the inhibitors. In vitro screening of the top three compounds has resulted in the identification of one of the compounds (compound 3) which shows little cytotoxic effects. This compound therefore represents a good starting point for further in vivo experimentation and could possibly serve as an important drug candidate for the treatment of leishmaniasis.

scholarly journals Illustrating and homology modeling the proteins of the Zika virus

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 275 ◽  
Author(s):  
Sean Ekins ◽  
John Liebler ◽  
Bruno J. Neves ◽  
Warren G. Lewis ◽  
Megan Coffee ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Crystal Structures ◽  
Zika Virus ◽  
Antiviral Drug ◽  
Homology Model ◽  
Glycoprotein E ◽  
Starting Point ◽  
Homology Models

The Zika virus (ZIKV) is a flavivirus of the familyFlaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it eitherin vitroorin vivo. ZIKV therefore epitomizes a neglected disease. Several suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure-based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our criteria for selection. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening.

scholarly journals Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning

2020 ◽  
Author(s):  
Ayman Farag ◽  
Ping Wang ◽  
Mahmoud Ahmed ◽  
Hesham Sadek
Keyword(s):  
Drug Repositioning ◽  
Binding Energies ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Protease Enzyme ◽  
Starting Point ◽  
Approved Drugs ◽  
Fda Approved Drugs

<div>The new strain of Coronaviruses (SARS-CoV-2), and the resulting Covid-19 disease has spread swiftly across the globe after its initial detection in late December 2019 in Wuhan, China, resulting in a pandemic status declaration by WHO within 3 months. Given the heavy toll of this pandemic, researchers are actively testing various strategies including new and repurposed drugs as well as vaccines. In the current brief report, we adopted a repositioning approach using insilico molecular modeling screening using FDA approved drugs with established safety profiles for potential inhibitory effects on Covid-19 virus. We started with structure based drug design by screening more than 2000 FDA approved drugs</div><div>against Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket to identify potential hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications. In addition, we elucidate preliminary pharmacophore features for candidates bound to Covid-19 virus Mpro substratebinding pocket. The top hits include anti-viral drugs such as Darunavir, Nelfinavirand Saquinavir, some of which are already being tested in Covid-19 patients. Interestingly, one of the most promising hits in our screen is the hypercholesterolemia drug Rosuvastatin. These results certainly do not confirm or indicate antiviral activity, but can rather be used as a starting point for further in vitro and in vivo testing, either individually or in combination.</div>

scholarly journals Molecular docking and molecular dynamics simulation study of inositol phosphorylceramide synthase – inhibitor complex in leishmaniasis: Insight into the structure based drug design

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1610 ◽  
Author(s):  
Vineetha Mandlik ◽  
Shailza Singh
Keyword(s):  
Molecular Dynamics ◽  
Dynamics Simulation ◽  
Sphingolipid Metabolism ◽  
Drug Candidate ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Starting Point ◽  
Synthase Inhibitor

Inositol phosphorylceramide synthase (IPCS) has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis. Five coumarin derivatives were developed as inhibitors of IPCS protein. Molecular dynamics simulations of the complexes of IPCS with these inhibitors were performed which provided insights into the binding modes of the inhibitors. In vitro screening of the top three compounds has resulted in the identification of one of the compounds (compound 3) which shows little cytotoxic effects. This compound therefore represents a good starting point for further in vivo experimentation and could possibly serve as an important drug candidate for the treatment of leishmaniasis.

scholarly journals Identification of Natural Compounds (Proanthocyanidin and Rhapontin) as High-Affinity Inhibitor of SARS-CoV-2 Mpro and PLpro using Computational Strategies

2021 ◽  
Author(s):  
Mohamed AlAjmi ◽  
Asim Azhar ◽  
Sadaf Hasan ◽  
Abdullah Alshabr ◽  
Afzal Hussain ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Economic Loss ◽  
Natural Compounds ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Protein Inhibitor ◽  
Active Site Residues

IntroductionThe emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic loss. Amongst many proteins encoded by SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and Papain-like protease (PLpro) serve as an attractive drug target.Material and methodsWe screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). 50 top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal mol-1 against Mpro and ≤ -5.0 kcal mol-1 against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes.ResultsProanthocyanidin and Rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while Rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of Proanthocyanidin and Rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol.ConclusionsThis study's outcome may serve Proanthocyanidin and Rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validations by in vitro and in vivo studies.

Discovery of 3-Cinnamamido-N-Substituted Benzamides as Potential Antimalarial Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Haicheng Liu ◽  
Yushi Futamura ◽  
Honghai Wu ◽  
Aki Ishiyama ◽  
Taotao Zhang ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antimalarial Activity ◽  
In Vitro Assays ◽  
Compound Library ◽  
Antimalarial Agents ◽  
Phenotypic Screen ◽  
Ic50 Values ◽  
Substituted Benzamides

Background: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. Objective: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3-cinnamamido-N-substituted benzamides. Method: In this study, a screening of our compound library was carried out against the multidrug-sensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters’ 4-day suppressive test. Results: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 µM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 µM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective which might be ascribed to the poor solubility of these compounds. Conclusion: In this study, phenotypic screen of our compound library resulted in the first report of 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against P. falciparum 3D7 strain with IC50 values around 0.1 µM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.

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