Reinstating apoptosis using putative Bcl-xL natural product inhibitors: Molecular docking and ADMETox profiling investigations

Boyenle, Ibrahim Damilare; Ogunlana, Abdeen Tunde; Oyedele, Abdul-Quddus Kehinde; Babatunde, Olokodana Kazeem; Owolabi, Nurudeen Abiodun; Solahudeen, Malik; Aderenle, Oluwafemi Timothy; Oloyede, Taiwo; Adelusi, Temitope Isaac

doi:10.1016/j.jtumed.2022.10.014

Cited by 3 publications

(4 citation statements)

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“…Thus they can be said to possess low distribution potential via this channel. [54] As far as metabolism is concerned, the inhibitory potential of the selected compounds and Inabenfide on the Cytochrome P-450 (CYP450) family was considered as inhibition of the CYP450 isoforms especially the CYP3A4 and CYP2D6 isoforms can have several detrimental effects on drug metabolism. Furthermore, none of the selected compounds inhibit the crucial isoforms and it is also worth mentioning that the standard Inabenfide inhibits both isoforms.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it can be deduced from this that the selected compounds have an overall better metabolism profile compared to Inabenfide. [54] According to Zheng and his colleagues, the removal of a compound and its metabolites via excretion is important to prevent accumulation and eventual cytotoxicity due to accumulation. [55] The assessment of half-life and clearance descriptors showed that Meliantrol and Tamarixetin have high clearance rates while Inabenfide has a relatively low clearance rate and the probability of having a long Half-life was closer to 1 for Tamarixetin while it is very low for Meliantrol and of moderate value for Inabenfide.…”

Section: Discussionmentioning

confidence: 99%

“…It could be deduced from the analysis of distribution parameters that none of the selected compounds, including Inabenfide have a good chance of penetrating the BBB. Thus they can be said to possess low distribution potential via this channel [54] . As far as metabolism is concerned, the inhibitory potential of the selected compounds and Inabenfide on the Cytochrome P‐450 (CYP450) family was considered as inhibition of the CYP450 isoforms especially the CYP3A4 and CYP2D6 isoforms can have several detrimental effects on drug metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, none of the selected compounds inhibit the crucial isoforms and it is also worth mentioning that the standard Inabenfide inhibits both isoforms. Therefore, it can be deduced from this that the selected compounds have an overall better metabolism profile compared to Inabenfide [54] …”

Section: Discussionmentioning

confidence: 99%

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Molecular Mechanics with Generalized Born Surface Area (MMGBSA) Calculations and Docking Studies Unravel some Antimalarial Compounds Using Heme O Synthase as Therapeutic Target

Adelusi,

Bolaji,

Ojo

et al. 2023

ChemistrySelect

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The enzyme Heme O Synthase (HOS) is essential for producing heme A and heme O, which are critical for defense against reactive oxygen species, drug detoxification, gas synthesis, transport, and electron transport in Plasmodium species. It has become vital to discover inhibitory molecules/compounds/medicines that target the synthesis of heme due to the emergence of drug‐resistant strains of Plasmodium falciparum. Therefore, in this study, we employed molecular mechanics with Generalized Born surface area (MMGBSA) calculations and docking studies to investigate potential antimalarial compounds targeting HOS from antimalarial botanicals. Screening these compounds, we have identified 2 compounds; Meliantrol and Tamarixetin with better binding affinities (−8.4 Kcal/mol and −8.3 Kcal/mol respectively) than the current standard inhibitor(Inabenfide) of HOS (−8.0 Kcal/mol). The MMGBSA calculations provided insight into the thermodynamics of the binding process and helped identify key interactions responsible for the stability of the HOS‐ligand complex. In addition, the 2 compounds were further screened comparatively with the standard HOS inhibitor considering their protein‐ligand interaction profile and ADMET profile and these 2 selected compounds outperformed Inabenfide. Our results predict that these compounds are potential drug candidates with domiciled therapeutic functions against Malaria therefore, open doors for more experimental validations for drug development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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