DFT calculations, molecular docking, binding free energy analysis and cytotoxicity assay of 7,7-dimethylaporphine alkaloids with methylenedioxy ring in positions 1 and 2

Branches, Adjane Dalvana S.; da Silva, Jonathas N.; de Oliveira, Micael Davi L.; Bezerra, Daniel P.; Soares, Milena B.P.; Costa, Emmanoel V.; Oliveira, Kelson M.T.

doi:10.1016/j.comptc.2024.114483

Cited by 2 publications

(1 citation statement)

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“…The docking scores are often used for ranking the refined structures accompanied by structural clustering simulation [ 41 , 47 , 63 , 64 , 68 , 70 , 71 , 73 , 74 , 75 ]. As MD-based protocols can effectively incorporate the effects of explicit water molecules and the flexibility of both protein target and ligand [ 75 , 76 ], several studies have reported the use of MD simulations for improvement of the docked poses of various ligands [ 41 , 69 , 70 , 77 , 78 , 79 ] including peptides [ 47 , 65 , 67 , 68 , 69 , 70 , 71 , 75 , 80 ].…”

Section: Introductionmentioning

confidence: 99%

Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols

Bayarsaikhan,

Zsidó,

Börzsei

et al. 2024

IJMS

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Histones are keys to many epigenetic events and their complexes have therapeutic and diagnostic importance. The determination of the structures of histone complexes is fundamental in the design of new drugs. Computational molecular docking is widely used for the prediction of target–ligand complexes. Large, linear peptides like the tail regions of histones are challenging ligands for docking due to their large conformational flexibility, extensive hydration, and weak interactions with the shallow binding pockets of their reader proteins. Thus, fast docking methods often fail to produce complex structures of such peptide ligands at a level appropriate for drug design. To address this challenge, and improve the structural quality of the docked complexes, post-docking refinement has been applied using various molecular dynamics (MD) approaches. However, a final consensus has not been reached on the desired MD refinement protocol. In this present study, MD refinement strategies were systematically explored on a set of problematic complexes of histone peptide ligands with relatively large errors in their docked geometries. Six protocols were compared that differ in their MD simulation parameters. In all cases, pre-MD hydration of the complex interface regions was applied to avoid the unwanted presence of empty cavities. The best-performing protocol achieved a median of 32% improvement over the docked structures in terms of the change in root mean squared deviations from the experimental references. The influence of structural factors and explicit hydration on the performance of post-docking MD refinements are also discussed to help with their implementation in future methods and applications.

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