Virtual screening of drug inhibitors for Mycobacterium tuberculosis ASAD.
Journal name: World Journal of Pharmaceutical Research
Original article title: Virtual screening of drug like inhibitors against aspartate semialdehyde dehydrogenase of lysine/ dap pathway of mycobacterium tuberculosis
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Kaur D, Gutte M. and Panke S.
World Journal of Pharmaceutical Research:
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Full text available for: Virtual screening of drug like inhibitors against aspartate semialdehyde dehydrogenase of lysine/ dap pathway of mycobacterium tuberculosis
Source type: An International Peer Reviewed Journal for Pharmaceutical and Medical and Scientific Research
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Summary of article contents:
Introduction
Tuberculosis (TB) remains a significant global health threat, with Mycobacterium tuberculosis (MTB) being the primary causative agent. The disease claims nearly two million lives annually, particularly in developing nations, and the emergence of drug-resistant strains exacerbates the problem. The study discussed here focuses on exploring the lysine/diaminopimelate (DAP) biosynthetic pathway as a potential target for new drug development. This pathway is critical for amino acid and cell wall biosynthesis, making it an attractive focus for identifying novel drug targets against TB.
Inhibiting Aspartate Semialdehyde Dehydrogenase
One of the main focuses of the study is Aspartate semialdehyde dehydrogenase (ASADH), an enzyme that plays a crucial role in the lysine/DAP pathway. ASADH catalyzes the conversion of aspartyl phosphate to aspartate semialdehyde, a key intermediate in the synthesis of diaminopimelic acid, which is vital for bacterial cell wall construction. The researchers employed virtual screening techniques to identify potential inhibitors targeting ASADH. They generated two compound datasets for screening: one comprising aspartyl phosphate analogs and the other consisting of antibacterial compounds from the PubChem database.
Virtual Screening and Docking Procedures
In the screening process, a library of 76 aspartyl phosphate-like compounds and 9 antibacterial compounds was created and subjected to molecular docking. Initial docking studies indicated that several inhibitors showed stronger binding affinities than aspartyl phosphate, which served as a control. The docking results, particularly the free energy binding values, indicated that the selected compounds established favorable interactions with the active site of ASADH, notably through hydrogen bonding with residues such as Cys130, Lys227, Arg99, and His256.
Insights from Docking with NADPH Complex
Following the success of docking with ASADH alone, the researchers advanced to docking the most promising inhibitors within the ASADH-NADPH complex. NADPH acts as a cofactor for ASADH, and the interactions of the selected inhibitors with this complex were evaluated. The best inhibitors demonstrated a significant binding energy range of -6.28 to -2.38 kcal/mol, outperforming the binding energy of aspartyl phosphate alone (-2.38 kcal/mol). This indicates the potential of these identified inhibitors in successfully competing for the active site in a biologically relevant environment.
Conclusion
The study highlighted the urgent need for new anti-tubercular agents amid rising drug resistance and presented ASADH as a viable drug target within the lysine/DAP biosynthetic pathway. A systematic virtual screening approach led to the identification of several potent inhibitors that demonstrated greater binding affinity than aspartyl phosphate, both in isolation and within the ASADH-NADPH complex. Although further experimental validation is necessary to advance these compounds as lead candidates for drug development, the insights gained through this research hold promise for the creation of novel therapeutic strategies against TB.
FAQ section (important questions/answers):
What is the primary focus of this research study?
The study aims to evaluate Aspartate semialdehyde dehydrogenase (ASADH) as a drug target for developing inhibitors against Mycobacterium tuberculosis, particularly in light of rising antibiotic resistance.
Why is tuberculosis a global health concern?
Tuberculosis remains a leading cause of death worldwide, particularly in developing countries, often exacerbated by drug-resistant strains of Mycobacterium tuberculosis due to improper treatment protocols.
What metabolic pathway is targeted for drug development in this study?
The research targets the Lysine/DAP biosynthetic pathway, crucial for amino acid and cell wall biosynthesis in Mycobacterium tuberculosis, seeking to identify novel inhibitors to combat the disease.
What methods were used to identify potential inhibitors?
The study utilized virtual screening procedures, including molecular docking of compounds from two datasets, one of aspartyl phosphate analogues and another of antibacterial compounds from PubChem.
How many potential inhibitors were identified in the study?
A total of 76 potential drug-like inhibitors were screened, with several showing strong binding affinity against Mycobacterium tuberculosis ASADH, indicating their potential as lead compounds.
What was the binding energy of the best inhibitors found?
The top inhibitors exhibited binding energies ranging from -7.41 to -5.67 kcal/mol, which are significantly stronger than the control substrate, aspartyl phosphate, which had a binding energy of -5.1 kcal/mol.
Glossary definitions and references:
Scientific and Ayurvedic Glossary list for “Virtual screening of drug inhibitors for Mycobacterium tuberculosis ASAD.”. This list explains important keywords that occur in this article and links it to the glossary for a better understanding of that concept in the context of Ayurveda and other topics.
1) Drug:
A drug is a chemical substance used to treat, cure, prevent, or diagnose diseases. In the context of tuberculosis treatment, drugs target specific bacterial pathways to inhibit their growth or viability. The importance of drug development is underscored by the rising incidence of drug-resistant strains of Mycobacterium tuberculosis.
2) Tuberculosis:
Tuberculosis (TB) is a highly infectious disease caused by the bacterium Mycobacterium tuberculosis. It primarily affects the lungs but can impact other organs as well. TB remains a global health crisis, particularly in developing countries, where its transmission and prevalence continue to challenge public health systems.
3) Antibiotic (Antibacterial):
An antibiotic is a type of antibacterial drug used to treat infections by either killing bacteria or inhibiting their growth. The rising antibiotic resistance in bacteria like Mycobacterium tuberculosis highlights the need for new antibiotics, particularly those targeting unique pathways not found in human cells.
4) Study (Studying):
Studying involves systematic investigation into a subject to gain deeper insights. In this context, studying the properties of Mycobacterium tuberculosis, including its drug resistance mechanisms and metabolic pathways, is vital for identifying effective therapeutic targets for the development of new anti-tubercular agents.
5) Wall:
In this context, 'wall' typically refers to the bacterial cell wall, which serves as a protective barrier and is crucial for maintaining the cell’s integrity. Understanding the composition and synthesis of the mycobacterial cell wall is essential for targeting new anti-TB therapies since it is unique to bacteria.
6) Calculation:
Calculation involves determining numerical values from data, such as evaluating binding energies in molecular docking studies. This is critical in the context of drug design, where calculations can predict the strength of interactions between potential drug candidates and their target enzymes, such as ASADH in tuberculosis.
7) Disease:
A disease is a pathological condition of a bodily part, an emotional state, or an organism resulting from various causes. In this study, tuberculosis is highlighted as a significant disease, posing global health challenges, particularly due to the emergence of drug-resistant strains and the high mortality rate associated.
8) Table:
In scientific research, a table is a systematic arrangement of data or information, often in rows and columns. It facilitates the clear presentation of results, such as binding affinities of various inhibitors in this study, aiding researchers in comparing the efficacy of different drug candidates against TB.
9) Death:
Death in this context refers to the fatal outcome of diseases like tuberculosis, which claims millions of lives annually, particularly in developing nations. Understanding the factors leading to TB-related deaths informs public health strategies and emphasizes the urgent need for effective interventions and new treatments.
10) Beta:
Beta typically refers to beta compounds, which may be a form of a particular molecular structure or a classification of drugs. In the context of the study, beta as a term could reference the beta configuration in chemical compounds that might play a role in interactions with biological targets.
11) Similarity:
Similarity indicates how closely related or alike different compounds are in terms of structure or function. In drug discovery, analyzing the similarity among compounds helps identify potential candidates that could exhibit desired biological activities, facilitating the screening of inhibitors against Mycobacterium tuberculosis effectively.
12) Activity:
Activity in pharmacology refers to the biological effect exerted by a compound, such as its capability to inhibit or kill bacteria. In the study, the activity of inhibitors against ASADH is essential for determining their potential as new therapeutic agents for combating tuberculosis infection.
13) Species:
Species refer to distinct types of organisms capable of interbreeding. In this study, the focus on species pertains to Mycobacterium tuberculosis and its relatives, emphasizing the need for understanding both the biodiversity of pathogenic bacteria and the relevance of targeting their unique biochemical pathways in drug development.
14) India:
India is highlighted in this study as a significant location affected by tuberculosis, having high incidence rates of this disease. The urgency for novel anti-TB drugs is particularly noted in India, where controlling and combating the spread of drug-resistant strains is critical for public health.
15) Discussion:
Discussion encompasses the interpretation and elaboration on results obtained in a study. Within this context, the discussion highlights the implications of the virtual screening results, potential candidates for drug development, limitations, and avenues for future research targeting Mycobacterium tuberculosis.
16) Developing:
Developing refers to the process of creating and improving something over time. Here, it relates to the development of new drugs for tuberculosis, emphasizing the need for innovative therapeutic approaches to combat the growing challenge of antibiotic resistance in Mycobacterium tuberculosis.
17) Toxicity:
Toxicity refers to the degree to which a substance can harm living organisms. In the context of drug development for tuberculosis, it is crucial that potential inhibitors are assessed for toxicity to ensure they are effective against bacterial targets without causing harm to human cells and tissues.
18) Mutation:
Mutation is a change in the DNA sequence of an organism, which may lead to variations in traits. In tuberculosis, mutations in Mycobacterium tuberculosis can lead to antibiotic resistance, making it imperative to understand and address these genetic changes in the development of effective antitubercular drugs.
19) Epidemic:
An epidemic is a sudden increase in the number of cases of a disease beyond what is normally expected. Tuberculosis is referred to as an epidemic due to its widespread occurrence in certain regions, emphasizing the critical need for public health interventions and novel treatments to control its spread.
20) Killing (Killed):
Killing indicates the lethal impact of a pathogen or treatment on a host or bacterial species. In the context of tuberculosis, the ability of anti-bacterial drugs to kill Mycobacterium tuberculosis is essential for successful treatment outcomes, especially given the rise of drug-resistant strains that challenge existing therapies.
21) Family:
Family refers to a group of related organisms or a classification in biological taxonomy. In the context of Mycobacterium tuberculosis, understanding its family of bacteria helps in identifying potential drug targets and strategies, as it shares metabolic pathways and characteristics with other mycobacterial species.
22) Vina:
Vina refers to AutoDock Vina, a tool used for molecular docking studies. It is instrumental in predicting the binding affinity of small molecules to proteins, such as ASADH in Mycobacterium tuberculosis. Vina aids researchers in virtual screening processes to identify potential novel drug candidates effectively.
23) Rich (Rch):
Rich can denote abundance or complexity. In this research context, it can refer to a rich database of compounds available for screening and analysis. The rich assortment of drug-like compounds can provide a variety of potential inhibitors, enhancing the likelihood of discovering effective anti-tubercular therapies.
24) Line:
Line in this context could refer to 'first-line treatments,' which are the standard initial therapies for tuberculosis. These drugs are essential for managing TB cases effectively. However, due to rising resistance, new compounds targeting alternative pathways in Mycobacterium tuberculosis are actively being sought after to supplement traditional first-line therapies.
Other Science Concepts:
Discover the significance of concepts within the article: ‘Virtual screening of drug inhibitors for Mycobacterium tuberculosis ASAD.’. Further sources in the context of Science might help you critically compare this page with similair documents:
Experimental studies, Inhibitory activity, Molecular docking, Lipinski's Rule of Five, Active Site Prediction, Antibiotic resistance, High demand, Hydrogen bonding, Multidrug resistant Mycobacterium tuberculosis, Binding energy, Mycobacterium tuberculosis, Virtual screening, Drug resistant strains, Drug target, Lead compound, Novel drug, Metabolic pathway, Molecular modelling.