scholarly journals Molecular Informatics of Trypanothione Reductase of Leishmania major Reveals Novel Chromen-2-One Analogues as Potential Leishmanicides

2021 ◽  
Author(s):  
Samuel K. Kwofie ◽  
Gabriel B. Kwarko ◽  
Emmanuel Broni ◽  
Michael B. Adinortey ◽  
Michael D. Wilson
Keyword(s):  
Leishmania Major ◽  
Homology Modelling ◽  
Pharmacophore Model ◽  
Binding Energies ◽  
Dimensional Structure ◽  
Trypanothione Reductase ◽  
Pharmacophore Modelling ◽  
Drug Candidates ◽  
Dynamics Simulations

Trypanothione reductase (TR), a flavoprotein oxidoreductase is an important therapeutic target for leishmaniasis. Ligand-based pharmacophore modelling and molecular docking were used to predict selective inhibitors against TR. Homology modelling was employed to generate a three-dimensional structure of Leishmania major trypanothione reductase (LmTR). A pharmacophore model used to screen a natural compound library generated 42 hits, which were docked against the LmTR protein. Compounds with lower binding energies were evaluated via in silico pharmacological profiling and bioactivity. Four compounds emerged as potential leads comprising Karatavicinol (7-[(2E,6E,10S)-10,11-dihydroxy-3,7,11-trimethyldodeca-2,6-dienoxy]chromen-2-one), Marmin (7-[(E,6R)-6,7-dihydroxy-3,7-dimethyloct-2-enoxy]chromen-2-one), Colladonin (7-[[(4aS)-6-hydroxy-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]methoxy]chromen-2-one), and Pectachol (7-[(6-hydroxy-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl)methoxy]-6,8-dimethoxychromen-2-one) with good binding energies of −9.4, −9.3, 8.8, and −8.5 kcal/mol, respectively. These compounds bound effectively to the FAD domain of the protein with some critical residues including Asp35, Thr51, Lys61, Tyr198, and Asp327. Furthermore, molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) computations corroborated their strong binding. The compounds were also predicted to possess anti-leishmanial activity. The molecules serves as templates for the design of potential drug candidates and can be evaluated in vitro with optimistic results in producing plausible attenuating infectivity in macrophages.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

scholarly journals Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5593
Author(s):  
Katalin Szilágyi ◽  
Beáta Flachner ◽  
István Hajdú ◽  
Mária Szaszkó ◽  
Krisztina Dobi ◽  
...  
Keyword(s):  
Similarity Search ◽  
Pharmacophore Model ◽  
Cost Effective ◽  
Rapid Identification ◽  
Drug Candidates ◽  
Hit Rate ◽  
Physico Chemical ◽  
Cost Effective Approach ◽  
3D Methods

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach in early drug discovery. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compounds’ databases. This approach can be combined with physico-chemical parameter and diversity filtering, bioisosteric replacements, and fragment-based approaches for performing a first round biological screening. Our objectives were to investigate the combination of 2D similarity search with various 3D ligand and structure-based methods for hit expansion and validation, in order to increase the hit rate and novelty. In the present account, six case studies are described and the efficiency of mixing is evaluated. While sequentially combined 2D/3D similarity approach increases the hit rate significantly, sequential combination of 2D similarity with pharmacophore model or 3D docking enriched the resulting focused library with novel chemotypes. Parallel integrated approaches allowed the comparison of the various 2D and 3D methods and revealed that 2D similarity-based and 3D ligand and structure-based techniques are often complementary, and their combinations represent a powerful synergy. Finally, the lessons we learnt including the advantages and pitfalls of the described approaches are discussed.

Computational Discovery of SARS-CoV-2 NSP 16 Drug Candidates Based on Pharmacophore Modeling and Molecular Dynamics Simulation

2021 ◽  
Vol 20 (04) ◽  
pp. 377-390
Author(s):  
Zahra Hesari ◽  
Samaneh Zolghadri ◽  
Sajad Moradi ◽  
Mohsen Shahlaei ◽  
Elham Tazikeh-Lemeski
Keyword(s):  
Molecular Dynamics ◽  
Study Drug ◽  
Pharmacophore Modeling ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Drug Candidates ◽  
Computational Discovery ◽  
Approved Drugs ◽  
Dynamics Simulations

Non-Structural Protein 16 (NSP-16) is one of the most suitable targets for discovery of drugs for corona viruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been accomplished by pharmacophore-based virtual screening among some analogs (FDA approved drugs) and marine natural plants (MNP). The comparison of the binding energies and the inhibition constants was determined using molecular docking method. Three compounds including two FDA approved (Ibrutinib, Idelalisib) and one MNP (Kumusine) were selected for further investigation using the molecular dynamics simulations. The results indicated that Ibrutinib and Idelalisib are oral medications while Kumusine, with proper hydrophilic and solubility properties, is an appropriate candidate for nsp-16 inhibitor and can be effective to control COVID-19 disease.

scholarly journals Computationally designed synthetic peptides for transporter proteins imparts allostericity in Miltefosine resistant L. major

2020 ◽  
Vol 477 (10) ◽  
pp. 2007-2026
Author(s):  
Ritika Kabra ◽  
Prajakta Ingale ◽  
Shailza Singh
Keyword(s):  
Drug Resistance ◽  
Structure Prediction ◽  
Leishmania Major ◽  
Specific Binding ◽  
Parasite Load ◽  
Dimensional Structure ◽  
Oral Drug ◽  
Transporter Proteins

The emergence of drug resistance is a major concern for combating against Cutaneous Leishmaniasis, a neglected tropical disease affecting 98 countries including India. Miltefosine is the only oral drug available for the disease and Miltefosine transporter proteins play a pivotal role in the emergence of drug-resistant Leishmania major. The cause of resistance is less accumulation of drug inside the parasite either by less uptake of the drug due to a decrease in the activity of P4ATPase–CDC50 complex or by increased efflux of the drug by P-glycoprotein (P-gp, an ABC transporter). In this paper, we are trying to allosterically modulate the behavior of resistant parasite (L. major) towards its sensitivity for the existing drug (Miltefosine, a phosphatidylcholine analog). We have used computational approaches to deal with the conservedness of the proteins and apparently its three-dimensional structure prediction through ab initio modeling. Long scale membrane-embedded molecular dynamics simulations were carried out to study the structural interaction and stability. Parasite-specific motifs of these proteins were identified based on the machine learning technique, against which a peptide library was designed. The protein–peptide docking shows good binding energy of peptides Pg5F, Pg8F and PC2 with specific binding to the motifs. These peptides were tested both in vitro and in vivo, where Pg5F in combination with PC2 showed 50–60% inhibition in resistant L. major's promastigote and amastigote forms and 80–90% decrease in parasite load in mice. We posit a model system wherein the data provide sufficient impetus for being novel therapeutics in order to counteract the drug resistance phenotype in Leishmania parasites.

In silico modeling and in vitro activity of vitexin and isovitexin against SGLT2

2019 ◽  
Vol 18 (07) ◽  
pp. 1950035
Author(s):  
Yongheng Shi ◽  
Fancui Meng ◽  
Jiping Liu ◽  
Bin Wang
Keyword(s):  
Homology Model ◽  
Binding Mode ◽  
Positive Control ◽  
Binding Energies ◽  
In Vitro Test ◽  
In Silico Modeling ◽  
Vitro Test ◽  
Dynamics Simulations ◽  
Molecular Docking And Dynamics

The homology model of hSGLT2 (human sodium dependent glucose co-transporter 2) was used as a target for diabetes mellitus. Molecular docking and dynamics simulations were carried out on vitexin- and isovitexin-SGLT2 complexes with dapagliflozin as positive control. The results show that both vitexin and isovitexin have weaker binding energies compared to dapagliflozin, indicating that both ligands may exhibit weak anti-diabetic effects through inhibiting SGLT2. The poor binding mode of vitexin and isovitexin may be responsible for their weak anti-diabetic effect. These results are in accordance with the inhibitory activity against hSGLT2 in vitro test with the inhibitory rate 26.3% of vitexin and 11.2% of isovitexin at the dose of 10[Formula: see text][Formula: see text]mol[Formula: see text][Formula: see text][Formula: see text]L[Formula: see text]. The results of calculation and in vitro test may explain the possible inhibiting mechanism of vitexin and isovitexin against SGLT2, and therefore enhance our understanding of the structure-activity relationships of SGLT2 inhibitors.

scholarly journals Development of anEx VivoLymph Node Explant Model for Identification of Novel Molecules Active against Leishmania major

2013 ◽  
Vol 58 (1) ◽  
pp. 78-87 ◽  
Author(s):  
Alex G. Peniche ◽  
Yaneth Osorio ◽  
Adam R. Renslo ◽  
Doug E. Frantz ◽  
Peter C. Melby ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Drug Efficacy ◽  
Peritoneal Macrophages ◽  
Effective Concentration ◽  
Content Type ◽  
Drug Candidates ◽  
New Drug ◽  
Vector Borne

ABSTRACTLeishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using anex vivolymph nodeexplantculture (ELEC) derived from the draining lymph nodes ofLeishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infectedin vitrowithL. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active againstL. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC50). We found 24 compounds (7%) that had aninvitrotherapeuticindex (IVTI; 50% cytotoxic/effective concentration [CC50]/EC50) > 100; 19 of the compounds had an EC50below 1 μM. According to PubChem searchs, 17 of those compounds had not previously been reported to be active againstLeishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis.

scholarly journals Elucidation of Teicoplanin Interactions with Drug Targets Related to COVID-19

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 856
Author(s):  
Faizul Azam
Keyword(s):  
Binding Energy ◽  
Nucleocapsid Protein ◽  
Drug Targets ◽  
Bacterial Infections ◽  
Interaction Mechanism ◽  
Binding Energies ◽  
Ligand Complex ◽  
Average Binding Energy ◽  
Dynamics Simulations

Teicoplanin is a glycopeptide antibiotic effective against several bacterial infections, has exhibited promising therapeutic efficiency against COVID-19 in vitro, and the rationale for its use in COVID-19 is yet to be recognized. Hence, in this study a number of molecular modeling techniques were employed to decrypt the mechanistic insight of teicoplanin interaction with several COVID-19 drug targets. Initially, molecular docking was employed to study the teicoplanin interaction with twenty-five SARS-CoV-2 structural and non-structural proteins which was followed by molecular mechanics/generalized Born surface area (MM/GBSA) computation for binding energy predictions of top ten models from each target. Amongst all macromolecular targets, the N-terminal domain of the nucleocapsid protein displayed the strongest affinity with teicoplanin showing binding energies of −7.4 and −102.13 kcal/mol, in docking and Prime MM/GBSA, respectively. Thermodynamic stability of the teicoplanin-nucleocapsid protein was further probed by molecular dynamics simulations of protein–ligand complex as well as unbounded protein in 100 ns trajectories. Post-simulation MM-GBSA computation of 50 frames extracted from simulated trajectories estimated an average binding energy of −62.52 ± 12.22 kcal/mol. In addition, conformational state of protein in complex with docked teicoplanin displayed stable root-mean-square deviation/fluctuation. In conclusion, computational investigation of the potential targets of COVID-19 and their interaction mechanism with teicoplanin can guide the design of novel therapeutic armamentarium for the treatment of SARS-CoV-2 infection. However, additional studies are warranted to establish the clinical use or relapses, if any, of teicoplanin in the therapeutic management of COVID-19 patients.

scholarly journals 3-Methoxycarpachromene and Masticadienonic Acid as New Target Inhibitors from Pistacia atlantica Leaves against Trypanothione Reductase of Leishmania Parasites: In Vitro and In Silico Studies

2021 ◽  
Author(s):  
Saarra Maamri ◽  
Khedidja Benarous ◽  
Mohamed Yousfi
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Leishmania Major ◽  
Trypanothione Reductase ◽  
Binding Modes ◽  
Pistacia Atlantica ◽  
In Silico Studies ◽  
Ic50 Values ◽  
Leishmania Parasites

This study aimed to identify new drug molecules against Leishmania parasites, leishmaniasis's causal agent, using Pistacia atlantica leaves as source. The evaluation of the anti-leishmania potential against the promastigote form of Leishmania. infantum and Leishmania. major was performed. A new in silico study was accomplished using molecular docking, with Autodock vina program, to find the binding affinity of two important phytochemical compounds from this plant (Masticadienonic acid, 3-Methoxycarpachromene) towards the trypanothione reductase as target drugs, responsible for defence mechanism against oxidative stress and virulence of this parasites. Results: Several concentrations showed a significant decrease in cell viability (P<0.0001), with IC50 values of 0.3 mg/ mL for L. infantum and 0.12 mg/ mL L. major; The molecular docking confirms the significant relationship between Leishmania survival and the inhibition of this crucial enzyme. There were promising and new positive results on binding modes of selected ligands and the trypanothione reductase for the first time. Through this work, we propose 3-Methoxycarpachromene and Masticadienonic acid as anti Trypanosomatidae species drug.

scholarly journals Natural xanthone compounds as promising drug candidates against COVID-19 - An integrated molecular docking and dynamics simulation study

2020 ◽  
Author(s):  
Shravan Kumar Gunda ◽  
Hima Kumari P ◽  
Gourav Choudhir ◽  
Anuj Kumar ◽  
P B. Kavi Kishor ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Lipinski’S Rule ◽  
Drug Candidates ◽  
Main Protease ◽  
Lipinski’S Rule Of Five ◽  
Dynamics Simulations ◽  
Potential Inhibitors

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease2019 (COVID-19). SARS-CoV-2 is known for its high pathogenicity and transmission due to thepresence of polybasic cleavage sites. No specific drug is available for the treatment. To identifythe potential inhibitors, we have performed molecular docking against the SARS-CoV-2 mainprotease (6Y84) with fifteen important natural xanthone compounds. The docking results showedall the compounds exhibited good binding energies and interactions with the main protease. Thevalidation of representative docking complexes through molecular dynamics simulations showedthat xanthones binds with a higher binding affinity and lower free energy than the standardligand with Brasixanthone C and Brasixanthone B on 50 ns. Natural xanthone compounds havealso passed the Absorption, Distribution, Metabolism, and Excretion (ADME) property criteriaas well as Lipinski’s rule of five. The present integrated molecular docking and dynamicssimulations study unveil the use of xanthones as potential antiviral agents against SARS-CoV-2.

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