Identification of peptidomimetic compounds as potential inhibitors against MurA enzyme of Mycobacterium tuberculosis

Bhardwaj

Journal of Biomolecular Structure and Dynamics

et al. 2020

Self Cite

Given the COVID-19 pandemic, currently, there are many drugs in clinical trials against this virus. Among the excellent drug targets of SARS-CoV-2 are its proteases (Nsp3 and Nsp5) that plays vital role in polyprotein processing giving rise to functional nonstructural proteins, essential for viral replication and survival. Nsp5 (also known as M pro) hydrolyzes replicase polyprotein (1ab) at eleven different sites. For targeting M pro , we have employed drug repurposing approach to identify potential inhibitors of SARS-CoV-2 in a shorter time span. Screening of approved drugs through docking reveals Hyaluronic acid and Acarbose among the top hits which are showing strong interactions with catalytic site residues of M pro. We have also performed docking of drugs Lopinavir, Ribavirin, and Azithromycin on SARS-CoV-2 M pro. Further, binding of these compounds (Hyaluronic acid, Acarbose, and Lopinavir) is validated by extensive molecular dynamics simulation of 500 ns where these drugs show stable binding with M pro. We believe that the high-affinity binding of these compounds will help in designing novel strategies for structure-based drug discovery against SARS-CoV-2.

Section: Docking Studies Of M Pro With Approved Drugsmentioning

confidence: 99%

Reprofiling of approved drugs against SARS-CoV-2 main protease: an in-silico study

Bhardwaj

Journal of Biomolecular Structure and Dynamics

et al. 2020

Self Cite

“…The obtained ve-point pharmacophoremodel was used to screen zinc chemical database molecules to identify potent lead molecules against DprE1 enzyme. The resultant molecules recorded with dihydroquinonolin 2-one and Pyrazolo [1,5] pyramidin 5-one scaffold areutilized for the estimation of physicochemical properties and followed by binding mode analysis. The QuikProp study reveals that all hit molecules are associated with good pharmacokinetic properties and considered as prospective drug candidates for future research.…”

Section: Discussionmentioning

confidence: 99%

“…As per WHO report, nearly 10 million people infected and 1.4 million people died from tuberculosis in the year of 2019 [3]. India is the highest TB burden country accounting for more than 1/4 global incidence [4][5].…”

Section: Introductionmentioning

confidence: 99%

“…The resultant pharmacophore model was used to screen ZINC chemical database molecules to identify potent lead molecules against DprE1 enzyme. The resultant hit molecules were recorded with dihydroquinonolin 2one and Pyrazolo [1,5] pyramidin 5-one scaffold and this information could be helpful to design new potent anti-tuberculosis agent. Further, these molecules along with co-crystal ligand were utilized for the estimation of physicochemical properties and followed by binding mode analysis.…”

mentioning

confidence: 99%

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3D QSAR Pharmacophore Based Virtual Screening, ADME Analysis and Estimation of MM/GBSA binding Free Energies of Azoles as a Potential Inhibitor of DprE1 for Mycobacterium Tuberculosis

Madhavaram

Tigulla

2021

Preprint

Decaprenylphosphoryl - D – ribose – 2 –epimerase (DprE1) is a promising drug target to identify new anti- TB drugs against drug resistant tuberculosis. DprE1 helps in cell wall biosynthesis through Decaprenyl-phosphoryl d-arabinose pathway. Inhibition of DprE1 results in blocking of cell wall biosynthesis, causing death of mycobacterium tuberculosis. In current studies, a set of thirty triazole molecules having antitubercular activity were selected for pharmacophore 3D QSAR studies. The generated common pharmacophore hypothesis (AHRRR.172) consists of one acceptor (A), one hydrophobic (H), and three aromatic rings (R). The resulted pharmacophore model recorded with good statistical results, R2 = 0.71, Q2 = 0.54 and other parameters F = 45, RMSE = 0.41. This model further investigated to identify pharmacophoric features which are crucial for biological activity. The resultant pharmacophore model was used to screen ZINC chemical database molecules to identify potent lead molecules against DprE1 enzyme. The resultant hit molecules were recorded with dihydroquinonolin 2-one and Pyrazolo [1, 5] pyramidin 5-one scaffold and this information could be helpful to design new potent anti-tuberculosis agent. Further, these molecules along with co-crystal ligand were utilized for the estimation of physicochemical properties and followed by binding mode analysis.

“…The enzymes intricate in the microbial PG biosynthetic pathway are important as most of them do not have any similarities to the host. This further makes it optimal for selective targeting, subsequently enhancing its potential as a suitable drug target (Mdluli & Spigelman, 2006; Machowski et al., 2014; Kumar et al, 2020). Additionally, their indispensable nature and existence in Gram‐negative and Gram‐positive pathogens sites make them exceptional desires for broad‐spectrum antibiotics.…”

Section: Mtb Cell Envelopementioning

confidence: 99%

Glycoconjugates, hypothetical proteins, and post‐translational modification: Importance in host–pathogen interaction and antitubercular intervention development

Arega

Mahapatra

2021

Chem Biol Drug Des

With the emergence of multidrug‐resistant bacteria, insufficiency of the established chemotherapy, and the existing vaccine BCG, tuberculosis (TB) subsists as the chief cause of death in different parts of the world. Thus, identification of novel target proteins is urgently required to develop more effective TB interventions. However, the novel vaccine and drug target knowledge based on the essentiality of the pathogen cell envelope components such as glycoconjugates, glycans, and the peptidoglycan layer of the lipid‐rich capsule are limited. Furthermore, most of the genes encoding proteins are characterized as hypothetical and functionally unknown. Correspondingly, some researchers have shown that the lipid and sugar components of the envelope glycoconjugates are largely in charge of TB pathogenesis and encounter many drugs and vaccines. Therefore, in this review we provide an insight into a comprehensive study concerning the importance of cell envelope glycoconjugates and hypothetical proteins, the impact of post‐translational modification, and the bioinformatics‐based implications for better antitubercular intervention development.