Discovery of New Delhi Metallo-β-Lactamase-1(NDM-1) Inhibitors From Natural Compounds: In Silico-Based Methods

Abstract New Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for new Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with new Delhi metallo-β-lactamase. 3D conformational alignment and protein sequence alignment of all new Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Then the conserved and crucial residues in the catalytic activity of metallo-β-lactamases were detected. These residues had similar 3D coordinates in the 3D conformational alignment. So it is possible that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all new Delhi metallo-β-lactamase and metallo-β-lactamases in experimental studies.

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Discovery of potential inhibitors against New Delhi metallo-β-lactamase-1 from natural compounds: in silico-based methods

Scientific Reports ◽

10.1038/s41598-021-82009-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Azhar Salari-jazi ◽

Karim Mahnam ◽

Parisa Sadeghi ◽

Mohamad Sadegh Damavandi ◽

Jamshid Faghri

Keyword(s):

Binding Free Energy ◽

Experimental Studies ◽

Spatial Location ◽

Natural Compounds ◽

Pharmacophore Modeling ◽

Dynamics Simulation ◽

Health Concern ◽

Multi Drug Resistance ◽

New Delhi ◽

Almost All

AbstractNew Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for New Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35,032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with New Delhi metallo-β-lactamase. Protein sequence alignment, 3D conformational alignment, pharmacophore modeling on all New Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Quantum chemical perspective based on the fragment molecular orbital (FMO) method was performed to discover conserved and crucial residues in the catalytic activity of metallo-β-lactamases. These residues had similar 3D coordinates of spatial location in the 3D conformational alignment. So it is posibble that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all metallo-β-lactamases in experimental studies.

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Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for Pseudomonas aeruginosa Multiple Virulence Factor Regulator (MvfR)

Molecules ◽

10.3390/molecules26226811 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6811

Author(s):

Raed A. H. Almihyawi ◽

Halah M. H. Al-Hasani ◽

Tabarak Sabah Jassim ◽

Ziyad Tariq Muhseen ◽

Sitong Zhang ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Virulence Factor ◽

Experimental Studies ◽

Binding Mode ◽

Dynamics Simulation ◽

Multi Drug Resistance ◽

Binding Potential ◽

Virulence Proteins ◽

Long Run ◽

Therapeutic Molecules

Multi-drug resistance (MDR) bacterial pathogens pose a threat to global health and warrant the discovery of new therapeutic molecules, particularly those that can neutralize their virulence and stop the evolution of new resistant mechanisms. The superbug nosocomial pathogen, Pseudomonas aeruginosa, uses a multiple virulence factor regulator (MvfR) to regulate the expression of multiple virulence proteins during acute and persistent infections. The present study targeted MvfR with the intention of designing novel anti-virulent compounds, which will function in two ways: first, they will block the virulence and pathogenesis P. aeruginosa by disrupting the quorum-sensing network of the bacteria, and second, they will stop the evolution of new resistant mechanisms. A structure-based virtual screening (SBVS) method was used to screen druglike compounds from the Asinex antibacterial library (~5968 molecules) and the comprehensive marine natural products database (CMNPD) (~32 thousand compounds), against the ligand-binding domain (LBD) of MvfR, to identify molecules that show high binding potential for the relevant pocket. In this way, two compounds were identified: Top-1 (4-((carbamoyloxy)methyl)-10,10-dihydroxy-2,6-diiminiodecahydropyrrolo[1,2-c]purin-9-yl sulfate) and Top-2 (10,10-dihydroxy-2,6-diiminio-4-(((sulfonatocarbamoyl)oxy)methyl)decahydropyrrolo[1,2-c]purin-9-yl sulfate), in contrast to the co-crystallized M64 control. Both of the screened leads were found to show deep pocket binding and interactions with several key residues through a network of hydrophobic and hydrophilic interactions. The docking results were validated by a long run of 200 ns of molecular dynamics simulation and MM-PB/GBSA binding free energies. All of these analyses confirmed the presence of strong complex formation and rigorous intermolecular interactions. An additional analysis of normal mode entropy and a WaterSwap assay were also performed to complement the aforementioned studies. Lastly, the compounds were found to show an acceptable range of pharmacokinetic properties, making both compounds potential candidates for further experimental studies to decipher their real biological potency.

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Effects and Mechanisms of Tea for the Prevention and Management of Diabetes Mellitus and Diabetic Complications: An Updated Review

Antioxidants ◽

10.3390/antiox8060170 ◽

2019 ◽

Vol 8 (6) ◽

pp. 170 ◽

Cited By ~ 32

Author(s):

Jin-Ming Meng ◽

Shi-Yu Cao ◽

Xin-Lin Wei ◽

Ren-You Gan ◽

Yuan-Feng Wang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Experimental Studies ◽

Epidemiological Studies ◽

Mechanisms Of Action ◽

Health Concern ◽

High Morbidity ◽

Protective Effects ◽

Public Health Concern ◽

Β Cells ◽

Patients With Diabetes

Diabetes mellitus has become a serious and growing public health concern. It has high morbidity and mortality because of its complications, such as diabetic nephropathy, diabetic cardiovascular complication, diabetic neuropathy, diabetic retinopathy, and diabetic hepatopathy. Epidemiological studies revealed that the consumption of tea was inversely associated with the risk of diabetes mellitus and its complications. Experimental studies demonstrated that tea had protective effects against diabetes mellitus and its complications via several possible mechanisms, including enhancing insulin action, ameliorating insulin resistance, activating insulin signaling pathway, protecting islet β-cells, scavenging free radicals, and decreasing inflammation. Moreover, clinical trials also confirmed that tea intervention is effective in patients with diabetes mellitus and its complications. Therefore, in order to highlight the importance of tea in the prevention and management of diabetes mellitus and its complications, this article summarizes and discusses the effects of tea against diabetes mellitus and its complications based on the findings from epidemiological, experimental, and clinical studies, with the special attention paid to the mechanisms of action.

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Predicting the Potential Effect of E484K Mutation on the Binding of 28 Antibodies to the Spike Protein of SARS-CoV-2 by Molecular Dynamics Simulation and Free Energy Calculation

10.26434/chemrxiv.13897091.v1 ◽

2021 ◽

Cited By ~ 1

Author(s):

Leyun Wu ◽

Cheng Peng ◽

Zhijian Xu ◽

weiliang zhu

Keyword(s):

Free Energy ◽

Binding Affinity ◽

Immune Escape ◽

Binding Free Energy ◽

Experimental Studies ◽

Potential Effect ◽

Dynamics Simulation ◽

Spike Protein ◽

Energy Calculation ◽

Potential Impact

Vaccines and antibody therapeutic are needed to fight the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has spread since 2020. Experimental studies have shown that the E484K variant may escape the neutralization of antibodies. To explore the potential impact of E484K mutation on the antibody binding affinity, we calculated the binding free energy of 28 antibodies to the wild type and K484 mutant of the spike protein of SARS-CoV-2. We found that 71% of the antibodies show lower binding affinity to the E484K mutant, indicating the highly possible immune escape risk of the mutated virus. Further analysis revealed that the other mutations, e.g. F490 and V483, are also likely to cause immune escape.

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A Review on Present Scenario of COVID-19 in Bangladesh

10.20944/preprints202012.0661.v1 ◽

2020 ◽

Author(s):

Mohammad Rejaur Rahman ◽

Emran Hossain Sajib ◽

Ishtiak Malique Chowdhury ◽

Anik Banik ◽

Rahul Bhattacharya ◽

...

Keyword(s):

Healthcare System ◽

Public Awareness ◽

Health Sector ◽

Health Concern ◽

Public Health Concern ◽

Healthcare Facilities ◽

Initial Stage ◽

The Government ◽

Almost All ◽

Spread Of Infection

The COVID-19 pandemic caused by SARS-CoV-2 has been showing a speedy growth in the number of infected patients with a remarkable mortality rate, thus it has become a worldwide public health concern. From March 8, 2020, the disease was confirmed to start spreading in Bangladesh. Since then, people got infected so exponentially that the country positions at the list of top infected countries in the world. Therefore, the objective of this comprehensive review was representing overall scenario of COVID-19 in different sectors of Bangladesh, particularly prioritizing the health sector. Up to 14 September 2020, 339,332 confirmed cases and 4,759 deaths were reported. An alarming fact is that while the global mutation rate of coronavirus is 7.23 % in average, the rate is 12.6 % in Bangladesh. Although the government ruled preventive strategies such as nationwide lockdown, social distancing, contact monitoring, quarantine and isolation, it was difficult to implement those due to lack of public awareness, inappropriate attitudes and so on. Moreover, the overburdened healthcare system had a weak response at initial stage because of insufficient healthcare facilities. Consequently, this pandemic affected severely almost all the important sectors of the country, specifically the economy, agriculture and health sectors. Hence, focusing on healthcare system as well as maintaining social distance and other essential precautions can limit the spread of infection and help to alleviate the severity of the pandemic.

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Predicting the Potential Effect of E484K Mutation on the Binding of 28 Antibodies to the Spike Protein of SARS-CoV-2 by Molecular Dynamics Simulation and Free Energy Calculation

10.26434/chemrxiv.13897091 ◽

2021 ◽

Author(s):

Leyun Wu ◽

Cheng Peng ◽

Zhijian Xu ◽

weiliang zhu

Keyword(s):

Free Energy ◽

Binding Affinity ◽

Immune Escape ◽

Binding Free Energy ◽

Experimental Studies ◽

Potential Effect ◽

Dynamics Simulation ◽

Spike Protein ◽

Energy Calculation ◽

Potential Impact

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Natural Compounds Activities against SARS-CoV-2 Mpro through Bioinformatics Approaches for Development of Antivirus Candidates

Jurnal Kimia Sains dan Aplikasi ◽

10.14710/jksa.24.5.170-176 ◽

2021 ◽

Vol 24 (5) ◽

pp. 170-176

Author(s):

Taufik Muhammad Fakih

Keyword(s):

Binding Free Energy ◽

Natural Compounds ◽

Protein Docking ◽

Ligand Docking ◽

Angiotensin Converting Enzyme 2 ◽

Docking Simulations ◽

Main Protease ◽

Alternative Approach ◽

Therapeutic Mechanism ◽

Almost All

Coronavirus infection (COVID-19) caused by SARS-CoV-2 appears as a pandemic that has spread to almost all countries in the world. Antiviral therapy using natural compounds is one alternative approach to overcome this infectious disease. The therapeutic mechanism is proven effective against the main protease (Mpro) of SARS-CoV-2. This research aims to perform bioinformatics studies, including ligand-docking simulations and protein-protein docking simulations, to identify, evaluate, and explore five compounds' activity on SARS-CoV-2 Mpro and their effects against Angiotensin-Converting Enzyme 2 (ACE-2). Protein-ligand docking simulations show kaempferol, flavonol, and their glycosides (Afzelin and Juglanin) and other flavonoids (Quercetin, Naringenin, and Genistein) have a high affinity towards SARS-CoV-2 Mpro. These results were then confirmed using protein-protein docking simulations to observe the ability of five compounds to prevent the attachment of ACE-2 to the active site. Based on the results of the bioinformatics studies, Quercetin has the best affinity, with a binding free energy value of −33.18 kJ/mol. The five compounds are predicted to be able to interact strongly with SARS-CoV-2. The results in this research are useful for further studies in the development of novel anti-infective drugs for COVID-19 that target SARS-CoV-2 Mpro.

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Discovery of Non-Peptidic Compounds against Chagas Disease Applying Pharmacophore Guided Molecular Modelling Approaches

Molecules ◽

10.3390/molecules23123054 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3054 ◽

Cited By ~ 1

Author(s):

Shailima Rampogu ◽

Gihwan Lee ◽

Ayoung Baek ◽

Minky Son ◽

Chanin Park ◽

...

Keyword(s):

Chagas Disease ◽

Binding Free Energy ◽

Heart Diseases ◽

3D Qsar ◽

Binding Mode ◽

Natural Compounds ◽

Free Energy Calculations ◽

New Drugs ◽

Dynamics Simulation ◽

Discovery Studio

Chagas disease is one of the primary causes of heart diseases accounting to 50,000 lives annually and is listed as the neglected tropical disease. Because the currently available therapies have greater toxic effects with higher resistance, there is a dire need to develop new drugs to combat the disease. In this pursuit, the 3D QSAR ligand-pharmacophore (pharm 1) and receptor-based pharmacophore (pharm 2) search was initiated to retrieve the candidate compounds from universal natural compounds database. The validated models were allowed to map the universal natural compounds database. The obtained lead candidates were subjected to molecular docking against cysteine protease (PDB code: 1ME3) employing -Cdocker available on the discovery studio. Subsequently, two Hits have satisfied the selection criteria and were escalated to molecular dynamics simulation and binding free energy calculations. These Hits have demonstrated higher dock scores, displayed interactions with the key residues portraying an ideal binding mode complemented by mapping to all the features of pharm 1 and pharm 2. Additionally, they have rendered stable root mean square deviation (RMSD) and potential energy profiles illuminating their potentiality as the prospective antichagastic agents. The study further demonstrates the mechanism of inhibition by tetrad residues compromising of Gly23 and Asn70 holding the ligand at each ends and the residues Gly65 and Gly160 clamping the Hits at the center. The notable feature is that the Hits lie in close proximity with the residues Glu66 and Leu67, accommodating within the S1, S2 and S3 subsites. Considering these findings, the study suggests that the Hits may be regarded as effective therapeutics against Chagas disease.

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Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

Molecules ◽

10.3390/molecules26030674 ◽

2021 ◽

Vol 26 (3) ◽

pp. 674

Author(s):

Ziyad Tariq Muhseen ◽

Alaa R. Hameed ◽

Halah M. H. Al-Hasani ◽

Sajjad Ahmad ◽

Guanglin Li

Keyword(s):

Free Energy ◽

Binding Energy ◽

Binding Free Energy ◽

Binding Mode ◽

Natural Compounds ◽

Rational Drug Design ◽

Dynamics Simulation ◽

Antiviral Compounds ◽

Rational Drug ◽

Key Residues

SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection.

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Discovery of the Novel Inhibitor Against New Delhi Metallo-β-Lactamase Based on Virtual Screening and Molecular Modelling

International Journal of Molecular Sciences ◽

10.3390/ijms21103567 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3567 ◽

Cited By ~ 3

Author(s):

Xiyan Wang ◽

Yanan Yang ◽

Yawen Gao ◽

Xiaodi Niu

Keyword(s):

Virtual Screening ◽

Bacterial Resistance ◽

Competitive Inhibition ◽

Binding Free Energy ◽

Binding Mode ◽

Hydrolytic Activity ◽

Dynamics Simulation ◽

Energy Calculation ◽

New Delhi ◽

The Novel

New Delhi metallo-β-lactamase (NDM-1), one of the metallo-β-lactamases (MBLs), leads to antibiotic resistance in clinical treatments due to the strong ability of hydrolysis to almost all kinds of β-lactam antibiotics. Therefore, there is the urgent need for the research and development of the novel drug-resistant inhibitors targeting NDM-1. In this study, ZINC05683641 was screened as potential NDM-1 inhibitor by virtual screening and the inhibitor mechanism of this compound was explored based on molecular dynamics simulation. The nitrocefin assay showed that the IC50 value of ZINC05683641 was 13.59 ± 0.52 μM, indicating that the hydrolytic activity of NDM-1 can be obviously suppressed by ZINC05683641. Further, the binding mode of ZINC05683641 with NDM-1 was obtained by molecular modeling, binding free energy calculation, mutagenesis assays and fluorescence-quenching assays. As results, ILE-35, MET-67, VAL-73, TRP-93, CYS-208, ASN-220 and HIS-250 played the key roles in the binding of NDM-1 with ZINC05683641. Interestingly, these key residues were exactly located in the catalytic activity region of NDM-1, implying that the inhibitor mechanism of ZINC05683641 against NDM-1 was the competitive inhibition. These findings will provide an available approach to research and develop new drug against NDM-1 and treatment for bacterial resistance.

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