DNA-binding residues and binding mode prediction with binding-mechanism concerned models

AbstractSome of the main challenges faced in drug discovery are pocket flexibility and binding mode prediction. In this work, we explored the aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction by means of in silico approaches. We first investigated the Spindlin1 aromatic cage plasticity by analyzing the available crystal structures and through molecular dynamic simulations. Then we assessed the ability of rigid docking and flexible docking to rightly reproduce the binding mode of a known ligand into Spindlin1, as an example of a reader protein displaying flexibility in the binding pocket. The ability of induced fit docking was further probed to test if the right ligand binding mode could be obtained through flexible docking regardless of the initial protein conformation. Finally, the stability of generated docking poses was verified by molecular dynamic simulations. Accurate binding mode prediction was obtained showing that the herein reported approach is a highly promising combination of in silico methods able to rightly predict the binding mode of small molecule ligands in flexible binding pockets, such as those observed in some reader proteins.

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Binding mode and affinity studies of DNA-binding agents using topoisomerase I DNA unwinding assay

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2006.11.038 ◽

2007 ◽

Vol 17 (4) ◽

pp. 1013-1017 ◽

Cited By ~ 22

Author(s):

Ruel E. McKnight ◽

Aaron B. Gleason ◽

James A. Keyes ◽

Sadia Sahabi

Keyword(s):

Dna Binding ◽

Topoisomerase I ◽

Binding Mode ◽

Dna Unwinding ◽

Binding Agents ◽

Dna Binding Agents

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DNA-binding mechanism of the Escherichia coli Ada O6-alkylguanine-DNA alkyltransferase

Nucleic Acids Research ◽

10.1093/nar/28.19.3710 ◽

2000 ◽

Vol 28 (19) ◽

pp. 3710-3718 ◽

Cited By ~ 11

Author(s):

P. E. Verdemato

Keyword(s):

Escherichia Coli ◽

Dna Binding ◽

Binding Mechanism ◽

Dna Alkyltransferase

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Evaluation of the Anticancer and DNA-Binding Characteristics of Dichloro(diimine)zinc(II) Complexes

Chemistry ◽

10.3390/chemistry3040086 ◽

2021 ◽

Vol 3 (4) ◽

pp. 1178-1188

Author(s):

Bandar A. Babgi ◽

Doaa Domyati ◽

Magda H. Abdellattif ◽

Mostafa A. Hussien

Keyword(s):

Dna Binding ◽

Binding Constants ◽

Docking Study ◽

Binding Mode ◽

Molecular Docking Study ◽

Binding Characteristics ◽

Anticancer Properties ◽

Amino Phenol ◽

Donor Acceptor ◽

Diimine Complexes

Several metal diimine complexes have been reported to possess anticancer properties. To evaluate the anticancer properties of tetrahedral zinc(II) diimine complexes, six complexes were synthesized with the general formula M(N^N)Cl2 {where M = Zn, Pt and N^N = 2,2’-biquinoline (1), 2,2’-dipyridylketone (2) and 4-((pyridine-2-ylmethylene)amino)phenol (3)}. In general, the intrinsic DNA-binding constants for the different compounds exhibited values within close proximity; the changes in the viscosity of the CT-DNA upon binding to the compounds suggest intercalation-binding mode. Molecular docking study predicted that complexes containing the highly planar ligand 2,2’-biquinoline are capable to establish π–π interactions with nucleobases of the DNA; the other four complexes engaged in donor–acceptor interactions with DNA nucleobases. The six complexes and two reference drugs (cisplatin and sunitinib) were tested against two cancer cell lines (COLO 205 and RCC-PR) and one normal cell line (LLC-MK2), highlighting the better performance of the zinc(II) complexes compared to their platinum(II) analogues. Moreover, zinc(II) complexes have higher selectivity index values than the reference drugs, with promising anticancer properties.

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Dissimilar Ligands Bind in a Similar Fashion: A Guide to Ligand Binding-Mode Prediction with Application to CELPP Studies

International Journal of Molecular Sciences ◽

10.3390/ijms222212320 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12320

Author(s):

Xianjin Xu ◽

Xiaoqin Zou

Keyword(s):

Molecular Similarity ◽

Complex Structure ◽

Binding Mode ◽

Molecular Structures ◽

Complex Structures ◽

Binding Modes ◽

Ligand Complex ◽

Systematic Analysis ◽

Binding Mode Prediction ◽

Similarity Principle

The molecular similarity principle has achieved great successes in the field of drug design/discovery. Existing studies have focused on similar ligands, while the behaviors of dissimilar ligands remain unknown. In this study, we developed an intercomparison strategy in order to compare the binding modes of ligands with different molecular structures. A systematic analysis of a newly constructed protein–ligand complex structure dataset showed that ligands with similar structures tended to share a similar binding mode, which is consistent with the Molecular Similarity Principle. More importantly, the results revealed that dissimilar ligands can also bind in a similar fashion. This finding may open another avenue for drug discovery. Furthermore, a template-guiding method was introduced for predicting protein–ligand complex structures. With the use of dissimilar ligands as templates, our method significantly outperformed the traditional molecular docking methods. The newly developed template-guiding method was further applied to recent CELPP studies.

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