Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers

While orthosteric ligands of the angiotensin II (AngII) type 1 receptor (AT1R) are available for clinical and research applications, allosteric ligands are not known for this important G protein-coupled receptor (GPCR). Allosteric ligands are useful tools to modulate receptor pharmacology and subtype selectivity. Here, we report AT1R allosteric ligands for a potential application to block autoimmune antibodies. The epitope of autoantibodies for AT1R is outside the orthosteric pocket in the extracellular loop 2. A molecular dynamics simulation study of AT1R structure reveals the presence of a druggable allosteric pocket encompassing the autoantibody epitope. Small molecule binders were then identified for this pocket using structure-based high-throughput virtual screening. The top 18 hits obtained inhibited the binding of antibody to AT1R and modulated agonist-induced calcium response of AT1R. Two compounds out of 18 studied in detail exerted a negative allosteric modulator effect on the functions of the natural agonist AngII. They blocked antibody-enhanced calcium response and reactive oxygen species production in vascular smooth muscle cells as well as AngII-induced constriction of blood vessels, demonstrating their efficacy in vivo. Our study thus demonstrates the feasibility of discovering inhibitors of the disease-causing autoantibodies for GPCRs. Specifically, for AT1R, we anticipate development of more potent allosteric drug candidates for intervention in autoimmune maladies such as preeclampsia, bilateral adrenal hyperplasia, and the rejection of organ transplants.

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A computational biology approach for the identification of potential SARS-CoV-2 main protease inhibitors from natural essential oil compounds.

F1000Research ◽

10.12688/f1000research.73999.1 ◽

2021 ◽

Vol 10 ◽

pp. 1313

Author(s):

Rizone Al Hasib ◽

Md. Chayan Ali ◽

Md. Shahedur Rahman ◽

Md. Mafizur Rahman ◽

Fee Faysal Ahmed ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Essential Oil ◽

New Drugs ◽

Dynamics Simulation ◽

World Health ◽

Drug Candidates ◽

Main Protease ◽

Essential Oil Compounds

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has fomented a climate of fear worldwide due to its rapidly spreading nature, and high mortality rate. The World Health Organization (WHO) declared it as a global pandemic on 11th March, 2020. Many endeavors have been made to find appropriate medications to restrain the SARS CoV-2 infection from spreading but there is no specific antiviral therapy to date. However, a computer-aided drug design approach can be an alternative to identify probable drug candidates within a short time. SARS-CoV-2 main protease is a proven drug target, and it plays a pivotal role in viral replication and transcription. Methods: In this study, we identified a total of 114 essential oil compounds as a feasible anti-SARS-CoV-2 agent from several online reservoirs. These compounds were screened by incorporating ADMET profiling, molecular docking, and 50 ns of molecular dynamics simulation to identify potential drug candidates against the SARS-CoV-2 main protease. The crystallized SARS-CoV-2 main protease structure was collected from the RCSB PDB database (PDB ID 6LU7). Results: According to the results of the ADMET study, none of the compounds have any side effects that could reduce their druglikeness or pharmacokinetic properties. Out of 114 compounds, we selected bisabololoxide B, eremanthin, and leptospermone as our top drug candidates based on their higher binding affinity scores, and strong interaction with the Cys 145-His 41 catalytic dyad. Finally, the molecular dynamics simulation was implemented to evaluate the structural stability of the ligand-receptor complex. MD simulations disclosed that all the hits showed conformational stability compared to the positive control α-ketoamide. Conclusions: Our study showed that the top three hits might work as potential anti-SARS-CoV-2 agents, which can pave the way for discovering new drugs, but for experimental validation, they will require more in vivo trials.

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Identification of Potential Phytochemical Inhibitors as Promising Therapeutics Against SARS-CoV-2 and Molecular Dynamics Simulation

10.26434/chemrxiv.13182965.v1 ◽

2020 ◽

Author(s):

Anik Banik ◽

Emran Sajib ◽

Anamika Deb ◽

Sheikh Rashel Ahmed ◽

Md- Tariqul Islam ◽

...

Keyword(s):

Molecular Dynamics ◽

Rna Binding ◽

Viral Infections ◽

Dynamics Simulation ◽

Screening Methods ◽

Plant Metabolites ◽

Target Class ◽

Drug Candidates ◽

Preventive Medication

The high infectivity and mortality of novel coronavirus has caused a serious concern all over the world. Still, there is no specific drug or preventive medication to treat SARS-CoV-2 infection despite comprehensive analysis by the researchers. This study was designed to demonstrate the efficacy of some phyto-chemical compounds against SARS-CoV-2 by using both structure and ligand based virtual screening methods. A total of 33 plant metabolites were screened against SARS-CoV-2 main protease proteins (MPP), Nsp9 RNA binding protein, spike receptor binding domain and HR2 domain using a molecular docking approach. Results showed that three metabolites, i.e., Limonin, Isoflavone, and Coumadin conferred maximum binding affinity with all key proteins of SARS-CoV-2. For each viral protein, the critical binding sites and drug surface hotspots have been unraveled. ADME analysis indicated that none of the compounds have adverse effects that could decrease their drug-like properties. Moreover, toxicity pattern analysis also unmasked the non-toxic nature of the top drug candidates. The RMSD values of top ligandmacromolecule complexes were less than 2 Å, while RMSF values showed regular atomic fluctuations in the molecular dynamics study. Notably, most of the target class by top drug candidates belonged to enzyme groups (e.g. oxidoreductases, protease, Kinase). Results of drug similarity prediction revealed two approved structural analogs of Coumadin named Warfarin (DB00682) and Phenprocoumon (DB00946) from DrugBank. In addition, Isoformononetin an experimental drug analog of isoflavone could also be an option for the treatment of viral infections. For limonin there was no analog found in drugbank. The study can pave the way for the creation of effective SARS-CoV-2 medications and preventive measures. We highly recommend further in vivo trials for the experimental validation of our findings

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Identification of Potential Phytochemical Inhibitors as Promising Therapeutics Against SARS-CoV-2 and Molecular Dynamics Simulation

10.26434/chemrxiv.13182965 ◽

2020 ◽

Author(s):

Anik Banik ◽

Emran Sajib ◽

Anamika Deb ◽

Sheikh Rashel Ahmed ◽

Md- Tariqul Islam ◽

...

Keyword(s):

Molecular Dynamics ◽

Rna Binding ◽

Viral Infections ◽

Dynamics Simulation ◽

Screening Methods ◽

Plant Metabolites ◽

Target Class ◽

Drug Candidates ◽

Preventive Medication

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Recent Advances in the Development of Antimicrobial Peptides (AMPs): Attempts for Sustainable Medicine?

Current Medicinal Chemistry ◽

10.2174/0929867325666180117142142 ◽

2018 ◽

Vol 25 (21) ◽

pp. 2503-2519 ◽

Cited By ~ 4

Author(s):

Anne Kokel ◽

Marianna Torok

Keyword(s):

Side Effects ◽

Antimicrobial Peptides ◽

Potential Drug ◽

Green Technologies ◽

Specific Antibodies ◽

Structural Modifications ◽

Drug Candidates ◽

Induce Resistance ◽

Conventional Antibiotics

Background: Since the first isolation of antimicrobial peptides (AMPs) they have attracted extensive interest in medicinal chemistry. However, only a few AMP-based drugs are currently available on the market. Despite their effectiveness, biodegradability, and versatile mode of action that is less likely to induce resistance compared to conventional antibiotics, AMPs suffer from major issues that need to be addressed to broaden their use. Notably, AMPs can lack selectivity leading to side effects and cytotoxicity, and also exhibit in vivo instability. Several strategies are being actively considered to overcome the limitations that restrain the success of AMPs. Methods: In the current work, recent strategies reported for improving AMPs in the context of drug design and delivery were surveyed, and also their possible impact on patients and the environment was assessed. Results: As a major advantage AMPs possess an easily tunable skeleton offering opportunities to improve their properties. Strategic structural modifications and the beneficial properties of cyclic or branched AMPs in term of stability have been reported. The conjugation of AMPs with nanoparticles has also been explored to increase their in vivo stability. Other techniques such as the coupling of AMPs with specific antibodies aim to increase the selectivity of the potential drug towards the target. These strategies were evaluated for their effect on the environment highlighting green technologies. Conclusion: Although further research is needed taking into account both environmental and human health consequences of novel AMPs, several of these compounds are promising drug candidates for use in sustainable medicine.

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Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

Current Medicinal Chemistry ◽

10.2174/0929867325666181001115225 ◽

2019 ◽

Vol 26 (25) ◽

pp. 4799-4831 ◽

Cited By ~ 4

Author(s):

Jiahua Cui ◽

Xiaoyang Liu ◽

Larry M.C. Chow

Keyword(s):

Molecular Mechanisms ◽

Metastatic Cancer ◽

Drug Candidates ◽

Chemical Structures ◽

Transporter Family ◽

Promising Area ◽

New Generation ◽

Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

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Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666191010144111 ◽

2019 ◽

Vol 22 (8) ◽

pp. 509-520

Author(s):

Cauê B. Scarim ◽

Chung M. Chin

Keyword(s):

Drug Discovery ◽

Chagas Disease ◽

Drug Candidates ◽

Lead Compounds ◽

New Drug ◽

Compound Libraries ◽

Screening Assays ◽

Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Molecules ◽

10.3390/molecules26092505 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2505

Author(s):

Raheem Remtulla ◽

Sanjoy Kumar Das ◽

Leonard A. Levin

Keyword(s):

Machine Learning ◽

Neural Networks ◽

In Silico ◽

Disulfide Bonds ◽

Oral Absorption ◽

In Vivo Studies ◽

Drug Candidates ◽

In Silico Methods

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

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Ways into Understanding HIF Inhibition

Cancers ◽

10.3390/cancers13010159 ◽

2021 ◽

Vol 13 (1) ◽

pp. 159

Author(s):

Tina Schönberger ◽

Joachim Fandrey ◽

Katrin Prost-Fingerle

Keyword(s):

Protein Interactions ◽

Target Genes ◽

Protein Protein Interactions ◽

Low Oxygen ◽

Drug Candidates ◽

Open Questions ◽

Wide Range ◽

Hif Pathway

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.

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Evaluation of Browning Agents on the White Adipogenesis of Bone Marrow Mesenchymal Stromal Cells: A Contribution to Fighting Obesity

Cells ◽

10.3390/cells10020403 ◽

2021 ◽

Vol 10 (2) ◽

pp. 403

Author(s):

Girolamo Di Maio ◽

Nicola Alessio ◽

Ibrahim Halil Demirsoy ◽

Gianfranco Peluso ◽

Silverio Perrotta ◽

...

Keyword(s):

Bone Marrow ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

White Adipocyte ◽

Drug Candidates ◽

Fat Depots ◽

Treatment Of Obesity ◽

White Fat

Brown-like adipocytes can be induced in white fat depots by a different environmental or drug stimuli, known as “browning” or “beiging”. These brite adipocytes express thermogenin UCP1 protein and show different metabolic advantages, such as the ability to acquire a thermogenic phenotype corresponding to standard brown adipocytes that counteracts obesity. In this research, we evaluated the effects of several browning agents during white adipocyte differentiation of bone marrow-derived mesenchymal stromal cells (MSCs). Our in vitro findings identified two compounds that may warrant further in vivo investigation as possible anti-obesity drugs. We found that rosiglitazone and sildenafil are the most promising drug candidates for a browning treatment of obesity. These drugs are already available on the market for treating diabetes and erectile dysfunction, respectively. Thus, their off-label use may be contemplated, but it must be emphasized that some severe side effects are associated with use of these drugs.

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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

Applied Biological Chemistry ◽

10.1186/s13765-020-00564-4 ◽

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.

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