Repurposing of FDA-Approved drugs to predict new inhibitors against key regulatory genes in Mycobacterium Tuberculosis

Tuberculosis (TB) is one of the most dreadful and deadliest diseases, killing millions annually. Its causative organism is a bacterium called Mycobacterium tuberculosis which primarily attacks the lungs. Tuberculosis can be classified as latent and active based on the presence/absence of the clinical manifestations. Also known as active TB, pulmonary TB is characterized by extreme infection, whereas in latent TB, no infection or symptom is seen. In this in silico study, we focus on the molecular docking-based virtual screening of 10 FDA-approved drugs which already used to treat bacterial infections against target methoxy mycolic acid synthase 4 (MMA4) and cyclopropane mycolic acid synthase (CmaA2). Drug-resistant TB is the most challenging factor for the design and formulation of anti-tuberculosis drugs. Mycolic acid plays a crucial role in the pathogenesis of TB and, therefore, can be an extremely valuable target. Based on a study conducted on mice, by rendering the hma genes (MMA4 and cmaA) inactive, no synthesis of mycolic acid is observed. The binding energy scores of each ligand docked against the target shows the affinity that happens against the Tuberculosis disease.

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Recognizing drug targets using evolutionary information: implications for repurposing FDA-approved drugs against Mycobacterium tuberculosis H37Rv

Molecular BioSystems ◽

10.1039/c5mb00476d ◽

2015 ◽

Vol 11 (12) ◽

pp. 3316-3331 ◽

Cited By ~ 11

Author(s):

Gayatri Ramakrishnan ◽

Nagasuma R. Chandra ◽

Narayanaswamy Srinivasan

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Targets ◽

Drug Repurposing ◽

Target Space ◽

Evolutionary Information ◽

Mycobacterium Tuberculosis H37rv ◽

The Past ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Computational Drug Discovery

Drug repurposing to explore target space has been gaining pace over the past decade with the upsurge in the use of systematic approaches for computational drug discovery.

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Repurposing of FDA-approved drugs to target MurB and MurE enzymes in Mycobacterium tuberculosis

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1637280 ◽

2019 ◽

Vol 38 (9) ◽

pp. 2521-2532 ◽

Cited By ~ 5

Author(s):

Jyoti Rani ◽

Yumnam Silla ◽

Kasmika Borah ◽

Srinivasan Ramachandran ◽

Urmi Bajpai

Keyword(s):

Mycobacterium Tuberculosis ◽

Approved Drugs ◽

Fda Approved Drugs

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Molecular docking, molecular dynamics and MM/PBSA studies of FDA approved drugs for protein kinase a of Mycobacterium tuberculosis; application insights of drug repurposing

Informatics in Medicine Unlocked ◽

10.1016/j.imu.2019.100210 ◽

2019 ◽

Vol 16 ◽

pp. 100210 ◽

Cited By ~ 2

Author(s):

Shobana Sundar ◽

Lokesh Thangamani ◽

Gowdham Manivel ◽

Praveen Kumar ◽

Shanmughavel Piramanayagam

Keyword(s):

Molecular Dynamics ◽

Mycobacterium Tuberculosis ◽

Molecular Docking ◽

Protein Kinase ◽

Protein Kinase A ◽

Drug Repurposing ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Kinase A

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Comparing the Metabolome of a Caribbean Sponge to 420 FDA Approved Drugs, a Molecular Networking Approach

Planta Medica ◽

10.1055/s-0033-1348616 ◽

2013 ◽

Vol 79 (10) ◽

Author(s):

H Houson ◽

J Schlesser ◽

J Beverage ◽

V Macherla ◽

E Esquenazi

Keyword(s):

Molecular Networking ◽

Approved Drugs ◽

Fda Approved Drugs

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Faculty Opinions recommendation of Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718495519.793497730 ◽

2014 ◽

Author(s):

Herbert Tanowitz ◽

Fabiana Machado

Keyword(s):

Trypanosoma Cruzi ◽

Drug Combinations ◽

Potent Drug ◽

Approved Drugs ◽

Synergy Testing ◽

Fda Approved Drugs

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Faculty Opinions recommendation of Combining Molecular Scaffolds from FDA Approved Drugs: Application to Drug Discovery.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727088776.793526189 ◽

2016 ◽

Author(s):

John Lowe

Keyword(s):

Drug Discovery ◽

Molecular Scaffolds ◽

Approved Drugs ◽

Fda Approved Drugs

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Targeting COVID-19 in Parkinson’s patients: Drugs repurposed.

Current Medicinal Chemistry ◽

10.2174/0929867327666200903115138 ◽

2020 ◽

Vol 27 ◽

Author(s):

Firoz Anwar ◽

Salma Naqvi ◽

Fahad A. Al-Abbasi ◽

Nauroz Neelofar ◽

Vikas Kumar ◽

...

Keyword(s):

Day Treatment ◽

Treatment Options ◽

Developed Countries ◽

Methyl Transferase ◽

Comt Inhibitors ◽

Mao B ◽

Pharmacokinetic Properties ◽

Us Fda ◽

Approved Drugs ◽

Fda Approved Drugs

: The last couple of months have witnessed the world in a state of virtual standstill. The SARS-CoV-2 virus has overtaken globe to economic and social lockdown. Many patients with COVID-19 have compromised immunity, especially in an aged population suffering from Parkinson disease (PD). Alteration in dopaminergic neurons or deficiency of dopamine in PD patients is the most common symptoms affecting 1% population above the age of 60 years. The compromised immune system and inflammatory manifestation in PD patients make them an easy target. The most common under trial drugs for COVID-19 are Remdesivir, Favipiravir, Chloroquine and Hydroxychloroquine, Azithromycin along with adjunct drugs like Amantadine with some monoclonal antibodies. : Presently, clinically US FDA approved drugs in PD includes Levodopa, catechol-O-methyl transferase (COMT) inhibitors, (Entacapone and Tolcapone), Dopamine agonists (Bromocriptine, Ropinirole, Pramipexole, and Rotigotine), Monoamine oxidase B (MAO-B) inhibitors (Selegiline and Rasagiline), Amantadine and Antimuscarinic drugs. The drugs have established mechanism of action on PD patients with known pharmacodynamics and pharmacokinetic properties along with dose and adverse effects. : Conclusion and relevance of this review focus on the drugs that can be tried for the PD patients with SAR CoV-2 infection, in particular, Amantadine approved by all developed countries a common drug possessing both antiviral properties by downregulation of CTSL, lysosomal pathway disturbance and change in pH necessary to uncoat the viral proteins and antiParkinson properties. The significant prognostic adverse effect of SARS-CoV-2 on PD and the present-day treatment options, clinical presentation and various mechanism is warrant need of the hour.

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Pd Catalyzed N1/N4 Arylation of Piperazine for Synthesis of Drugs, Biological and Pharmaceutical Targets: An Overview of Buchwald Hartwig Amination Reaction of Piperazine in Drug Synthesis

Current Organic Synthesis ◽

10.2174/1570179415666171206151603 ◽

2018 ◽

Vol 15 (2) ◽

pp. 208-220 ◽

Cited By ~ 3

Author(s):

Vaibhav Mishra ◽

Tejpal Singh Chundawat

Keyword(s):

Bond Formation ◽

Catalyst Design ◽

Biologically Active ◽

Reaction Conditions ◽

Biological Targets ◽

Amination Reaction ◽

Drug Synthesis ◽

Substituted Piperazine ◽

Approved Drugs ◽

Fda Approved Drugs

Background: Substituted piperazine heterocycles are among the most significant structural components of pharmaceuticals. N1/N4 substituted piperazine containing drugs and biological targets are ranked 3rd in the top most frequent nitrogen heterocycles in U.S. FDA approved drugs. The high demand of N1/N4 substituted piperazine containing biologically active compounds and U.S. FDA approved drugs, has prompted the development of Pd catalyzed C-N bond formation reactions for their synthesis. Buchwald-Hartwig reaction is the key tool for the synthesis of these compounds. Objective: This review provides strategies for Pd catalyzed C-N bond formation at N1/N4 of piperazine in the synthesis of drugs and biological targets with diverse use of catalyst-ligand system and reaction parameters. Conclusion: It is clear from the review that a vast amount of work has been done in the synthesis of N1/N4 substituted piperazine containing targets under the Pd catalyzed Buchwald-Hartwig amination of aryl halides by using different catalyst-ligand systems. These methods have become increasingly versatile as a result of innovation in catalyst design and improvements in reaction conditions. This review gives an overview of recent utilization of Buchwald-Hartwig amination reaction in drug/target synthesis.

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