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

Sundar, Shobana; Thangamani, Lokesh; Manivel, Gowdham; Kumar, Praveen; Shanmughavel, P.

doi:10.1016/j.imu.2019.100210

Cited by 21 publications

(13 citation statements)

References 23 publications

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“…Protein kinase A is recognized for its significant contribution in regulating the Mycobacterium cell shape and its mechanics. This protein gets exponentially upregulated during mycobacterial growth and infections [ 94 ]. Mycobacterial glutamine synthetase is known to increase the bacterium capacity to inhibit the host’s phagosome–lysosome defense mechanism.…”

Section: Computational Analysismentioning

confidence: 99%

Potential Anti-Mycobacterium tuberculosis Activity of Plant Secondary Metabolites: Insight with Molecular Docking Interactions

Kumar

Singh

et al. 2021

Antioxidants

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Tuberculosis (TB) is a recurrent and progressive disease, with high mortality rates worldwide. The drug-resistance phenomenon of Mycobacterium tuberculosis is a major obstruction of allelopathy treatment. An adverse side effect of allelopathic treatment is that it causes serious health complications. The search for suitable alternatives of conventional regimens is needed, i.e., by considering medicinal plant secondary metabolites to explore anti-TB drugs, targeting the action site of M. tuberculosis. Nowadays, plant-derived secondary metabolites are widely known for their beneficial uses, i.e., as antioxidants, antimicrobial agents, and in the treatment of a wide range of chronic human diseases (e.g., tuberculosis), and are known to “thwart” disease virulence. In this regard, in silico studies can reveal the inhibitory potential of plant-derived secondary metabolites against Mycobacterium at the very early stage of infection. Computational approaches based on different algorithms could play a significant role in screening plant metabolites against disease virulence of tuberculosis for drug designing.

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Section: Computational Analysismentioning

confidence: 99%

Potential Anti-Mycobacterium tuberculosis Activity of Plant Secondary Metabolites: Insight with Molecular Docking Interactions

Kumar

Singh

et al. 2021

Antioxidants

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“… [73] AutoDOCK 4.0 RmlD Carbohydrate biosynthesis Super Natural-II database – 570 compounds MD simulations – then ensemble docking No [74] CDOCKER BioA Biotin biosynthesis Enamine REAL database – 4.5 million compounds ADMET predictions In vivo confirmation against M. tuberculosis H37Rv [51] LdtB Peptidoglycan biosynthesis [75] FRIGATE Antigen 85c Lipid metabolism ZINC database – 2 million compounds No NMR binding against Antigen 85c and MIC against M. smegmatis [76] Glide LipU Lipid hydrolysis 6,282 FDA-approved drugs MD simulations and Prime MMGBSA calculations No [77] AroB Shikimate pathway 1,082 compounds preselected from DrugBank database MD simulations No [78] GlnA1 Glutamine biosynthesis ChEMBL antimycobacterials – 56,400; FDA-approved drugs – 1596; natural products – 419 & phytochemicals – 918. MD simulations and MMPBSA calculations No [79] DprE1 Arabinogalactan biosynthesis 30,789 ChEMBL antimycobacterial compounds ADME predictions; MD simulations and MMPBSA & MMGBSA calculations No [80] PknA Protein kinase 3,176 FDA-approved drugs MD simulations and MMPBSA calculations No [81] NarL Nitrate regulation 4,754 ChEMBL antimycobacterial compounds MD simulations and MMPBSA calculations No [52] …”

Section: Molecular Dockingmentioning

confidence: 99%

“…The calculation of drug-protein binding energies using MMPB(GB)SA has been applied to several drug discovery attempts against M. tuberculosis proteins. These include: LipU [77] , GlnA1 [79] , DprE1 [80] , PknA [81] , NarL [52] , PanC [141] , MurB [68] and MurE [68] . In the majority of cases, Glide was used to perform the initial virtual screen.…”

Section: Protein-ligand Binding Energiesmentioning

confidence: 99%

Structure-based in silico approaches for drug discovery against Mycobacterium tuberculosis

Kingdon

Alderwick

2021

Computational and Structural Biotechnology Journal

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“…This underlies intracellular regulatory mechanisms by which the bacterium responds to extracellular signals and adapt to changes in environmental conditions. Usually, post-translational modifications such as phosphorylation, ubiquitination, and acetylation describe mechanisms by which Mtb responds to oxidative stress induced by external factors [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Although numerous research efforts have been directed towards inhibiting either of these proteins, a recent paradigm shift has been aimed at the development of dual selective inhibitors that can simultaneously target both proteins [ 4 , 8 , 26 , 34 , 41 , 42 ]. This therapeutic approach presents an avenue to minimize the rate at which resistance occurs while at the same time increasing specificity.…”

Section: Introductionmentioning

confidence: 99%

Probing the Highly Disparate Dual Inhibitory Mechanisms of Novel Quinazoline Derivatives against Mycobacterium tuberculosis Protein Kinases A and B

Olotu

2020

Molecules

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Mycobacterium tuberculosis (Mtb) serine/threonine (Ser/Thr) Protein kinases A (PknA) and B (PknB) have been identified as highly attractive targets for overcoming drug resistant tuberculosis. A recent lead series optimization study yielded compound 33 which exhibited potencies ~1000 times higher than compound 57. This huge discrepancy left us curious to investigate the mechanistic ‘dual’ (in)activities of the compound using computational methods, as carried out in this study. Findings revealed that 33 stabilized the PknA and B conformations and reduced their structural activities relative to 57. Optimal stability of 33 in the hydrophobic pockets further induced systemic alterations at the P-loops, catalytic loops, helix Cs and DFG motifs of PknA and B. Comparatively, 57 was more surface-bound with highly unstable motions. Furthermore, 33 demonstrated similar binding patterns in PknA and B, involving conserved residues of their binding pockets. Both π and hydrogen interactions played crucial roles in the binding of 33, which altogether culminated in high ΔGs for both proteins. On the contrary, the binding of 57 was characterized by unfavorable interactions with possible repulsive effects on its optimal dual binding to both proteins, as evidenced by the relatively lowered ΔGs. These findings would significantly contribute to the rational structure-based design of novel and highly selective dual inhibitors of Mtb PknA and B.

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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

Cited by 21 publications

References 23 publications

Potential Anti-Mycobacterium tuberculosis Activity of Plant Secondary Metabolites: Insight with Molecular Docking Interactions

Potential Anti-Mycobacterium tuberculosis Activity of Plant Secondary Metabolites: Insight with Molecular Docking Interactions

Structure-based in silico approaches for drug discovery against Mycobacterium tuberculosis

Probing the Highly Disparate Dual Inhibitory Mechanisms of Novel Quinazoline Derivatives against Mycobacterium tuberculosis Protein Kinases A and B

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