Computational studies of the properties and activities of selected trisubstituted benzimidazoles as potential antitubercular drugs inhibiting MTB-FtsZ polymerization

Akinpelu, Olayinka I.; Lawal, Monsurat M.; Kumalo, Hezekiel M.; Mhlongo, Ndumiso N.

doi:10.1080/07391102.2020.1830176

Cited by 9 publications

(5 citation statements)

References 55 publications

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“…The RMSF calculations were estimated from the 100 ns trajectories of the systems and the results are shown in Figure 4. Similar to our previous studies on Mtb-FtsZ inhibition, 13,35 major differences in residue fluctuation in the systems were observed in residues 50-75, 120-140 and 230-270 which are the regions where the majority of the binding site residues are located. While the compounds' influences are observable almost on all the residues in the receptor, their effects are more noticeable on the residues closer to the binding pocket of the protein.…”

Section: Root Mean Square Fluctuation and Dssp Analysissupporting

confidence: 88%

“…It is worthy to note the importance of Phe 168 in the binding of ligands in almost all the systems (excluding the berb48 system). Previous computational studies13,35 also revealed Phe 168 as an important residue in the binding of other classes of compound (trisubstituted benzimidazoles and fusidic acid) to Mtb-FtsZ. Phe 168 is the highest contributing residue in berb9, berb37 and berb38 systems while it also contributes significantly to the binding of berb1 and berb43.…”

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confidence: 94%

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Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb‐FtsZ polymerisation through ligand‐based virtual screening and molecular dynamics simulations

Akinpelu

Kumalo

Mhlongo

et al. 2021

J of Molecular Recognition

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Berberine, an active compound in the extract of golden seal (an age-long remedy for many infections) has been confirmed to be responsible for the extract's activity against multi-drug resistant strain of Mycobacterium tuberculosis. There is no available study that shows the exact target of berberine in M tuberculosis, although it is confirmed that berberine inhibits the polymerisation of filamentous temperaturesensitive mutant Z (FtsZ), an important bacteria cytokinesis protein, in Escherichia coli, suggesting that FtsZ could as well be the target of berberine in M tuberculosis. In this study, we carried out ligand-based virtual screening to identify analogues of berberine followed by molecular dynamics (MD) simulations of the complexes of Mtb-FtsZ with berberine (berb1) and the five selected analogues (berb9 [ZINC1709414], berb37 [ZINC238749993], berb38 [ZINC13509022], berb43 [ZINC14765594], and berb48 [ZINC238758595]). Post-MD analyses such as binding free energy, RMSD, RMSF, RoG and hydrogen bond lifetime analysis were used to understand the interactions between these ligands and the receptor. The results suggested that Mtb-FtsZ could likely be the target of berberine in M tuberculosis as it forms a stable complex coupled with a significantly high binding energy. The study also identified other potential inhibitors of MTB-FtsZ polymerisation. Berb38 specifically showed greater interaction with the residues at the binding site of the protein, forming a far more stable complex with the receptor than any of the other compounds under investigation, including berberine itself. ADME properties calculations also predicted all the ligands to be bioactive as orally administered drugs.

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Section: Root Mean Square Fluctuation and Dssp Analysissupporting

confidence: 88%

mentioning

confidence: 94%

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb‐FtsZ polymerisation through ligand‐based virtual screening and molecular dynamics simulations

Akinpelu

Kumalo

Mhlongo

et al. 2021

J of Molecular Recognition

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“…We calculate some quantum chemical parameters of these complexes using a density functional theory (DFT) approach. The application of the DFT methods in estimating the chemical reactivity concepts of bioactive metal complexes is relevant. , Studies have shown its uses in calculating electron distribution to explore compounds’ reactivities. − We predict the potentials of these complexes as drug candidates using web-based software. The prediction guided our selection of cytochrome P450 3A4 (CYP3A4) to study the complexes’ inhibitory potency against this enzyme using our own N-layered integrated molecular orbital and molecular mechanics (ONIOM) method.…”

Section: Introductionmentioning

confidence: 99%

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

et al. 2021

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We report the synthesis and crystal structures of three new copper(II) Schiff-base complexes. The complexes have been characterized by elemental analysis and Fourier transform infrared (FT-IR) and UV–visible spectroscopies. The X-ray diffraction (XRD) analysis reveals that complexes 1 and 3 crystallize in a monoclinic space group C2/c and 2 in a triclinic space group P1̅, each adopting a square planar geometry around the metal center. We use a density functional theory method to explore the quantum chemical properties of these complexes. The calculation proceeds with the three-dimensional (3D) crystal structure characterization of the complexes in which the calculated IR and UV–vis values are comparable to the experimental results. Charge distribution and molecular orbital analyses enabled quantum chemical property prediction of these complexes. We study the drug-likeness properties and binding potentials of the synthesized complexes. The in silico outcome showed that they could serve as permeability-glycoprotein (P-gp) and different cytochrome P450 substrates. Our calculations showed that the complexes significantly bind to cytochrome P450 3A4.

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“…The SwissADME software was used for the boiled egg analysis [46]. The boiled egg analysis provides useful information about the BBB, HIA, PG+, and PG- [47]. The compounds that showed BBB permeability included linoleic acid, continentalic acid, magnolol, honokiol, alantolactone, berberine, coumarin, matrine, p-cumaric acid, ferulic acid, and vanillic acid while the rest of the compounds showed intestinal absorption, but no BBB permeability, as shown in Figure 3.…”

Section: Boiled Egg Analysismentioning

confidence: 99%

Anti-Inflammatory and Anti-Rheumatic Potential of Selective Plant Compounds by Targeting TLR-4/AP-1 Signaling: A Comprehensive Molecular Docking and Simulation Approaches

Khan

et al. 2022

Molecules

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Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic interactions. With TLR-4, rutin had the highest binding energy (−10.4 kcal/mol), poncirin had the highest binding energy (−9.4 kcal/mol) with NF-κB and JNK (−9.5 kcal/mol), respectively, and icariin had the highest binding affinity (−9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin’s greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood–brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties.

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Computational studies of the properties and activities of selected trisubstituted benzimidazoles as potential antitubercular drugs inhibiting MTB-FtsZ polymerization

Cited by 9 publications

References 55 publications

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb‐FtsZ polymerisation through ligand‐based virtual screening and molecular dynamics simulations

Identifying the analogues of berberine as promising antitubercular drugs targeting Mtb‐FtsZ polymerisation through ligand‐based virtual screening and molecular dynamics simulations

Design of New Schiff-Base Copper(II) Complexes: Synthesis, Crystal Structures, DFT Study, and Binding Potency toward Cytochrome P450 3A4

Anti-Inflammatory and Anti-Rheumatic Potential of Selective Plant Compounds by Targeting TLR-4/AP-1 Signaling: A Comprehensive Molecular Docking and Simulation Approaches

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