Elucidation of Binding Site and Chiral Specificity of Oxidovanadium Drugs with Lysozyme through Theoretical Calculations

Sciortino, Giuseppe; Sanna, Daniele; Ugone, Valeria; Micera, Giovanni; Lledós, Agustı́; Maréchal, Jean‐Didier; Garribba, Eugenio

doi:10.1021/acs.inorgchem.7b01732

Cited by 44 publications

(54 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, the results suggest that the docking methods could represent a new tool to predict metal complex–proteins interactions and could have a general applicability not only in medicinal but also in bioinorganic chemistry. For example, these methods were recently applied to predict the binding site of potential V IV O antidiabetic drugs with lysozyme …”

Section: Discussionmentioning

confidence: 99%

Prediction of the interaction of metallic moieties with proteins: An update for protein‐ligand docking techniques

et al. 2017

Self Cite

View full text Add to dashboard Cite

In this article, we present a new approach to expand the range of application of protein-ligand docking methods in the prediction of the interaction of coordination complexes (i.e., metallodrugs, natural and artificial cofactors, etc.) with proteins. To do so, we assume that, from a pure computational point of view, hydrogen bond functions could be an adequate model for the coordination bonds as both share directionality and polarity aspects. In this model, docking of metalloligands can be performed without using any geometrical constraints or energy restraints. The hard work consists in generating the convenient atom types and scoring functions. To test this approach, we applied our model to 39 high-quality X-ray structures with transition and main group metal complexes bound via a unique coordination bond to a protein. This concept was implemented in the protein-ligand docking program GOLD. The results are in very good agreement with the experimental structures: the percentage for which the RMSD of the simulated pose is smaller than the X-ray spectra resolution is 92.3% and the mean value of RMSD is < 1.0 Å . Such results also show the viability of the method to predict metal complexes-proteins interactions when the X-ray structure is not available. This work could be the first step for novel applicability of docking techniques in medicinal and bioinorganic chemistry and appears generalizable enough to be implemented in most protein-ligand docking programs nowadays available.

show abstract

Section: Discussionmentioning

confidence: 99%

Prediction of the interaction of metallic moieties with proteins: An update for protein‐ligand docking techniques

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…2 , activating one, two or three equatorial coordination positions, respectively, with dummy hydrogen atoms (Sciortino et al, 2017(Sciortino et al, , 2018a(Sciortino et al, ,b, 2019a. All the possible moieties…”

Section: Dft and Docking Calculationsmentioning

confidence: 99%

“…The scoring (Fitness of GoldScore) was calculated with the modified version of GoldScore scoring function, which was validated in previously published papers (Sciortino et al, 2017(Sciortino et al, , 2018a(Sciortino et al, , 2019a. The best solutions (binding poses) were evaluated through the mean (F mean ) and the highest value (F max ) of the Fitness associated with each pose, the population of the cluster containing the best pose and the position in the Fitness ranking of the computed cluster.…”

Section: Dft and Docking Calculationsmentioning

confidence: 99%

“…The second site (site B) is located in the Nterminal region, where His15 plus a water ligand are coordinated to the V IV O 2+ ion, and a hydrogen bond between V=O group and Thr89 stabilizes the binding. Interestingly, the His15 equatorial binding is not expected for bis-chelated cis moieties such as cis-V IV O(picolinato) 2 or cis-V IV O(maltolato) 2 due to the steric hindrance of the second ligand with an (equatorial-axial) arrangement (Sciortino et al, 2017). The third and fourth sites are weaker than these ones and are based on the coordination of (Asp18, Asn19) with F mean = 30.9 (site C) and (Asp119, Gln121) with F mean = 30.7 (site D).…”

Section: Interaction Of V Iii (Acac) 3 and V Iv O(acac) 2 With Proteinsmentioning

confidence: 99%

See 1 more Smart Citation

Biospeciation of Potential Vanadium Drugs of Acetylacetonate in the Presence of Proteins

et al. 2020

Self Cite

View full text Add to dashboard Cite

Among vanadium compounds with potential medicinal applications, [V IV O(acac) 2 ] is one of the most promising for its antidiabetic and anticancer activity. In the organism, however, interconversion of the oxidation state to +III and +V and binding to proteins are possible. In this report, the transformation of V III (acac) 3 , V IV O(acac) 2 , and V V O 2 (acac) − 2 after the interaction with two model proteins, lysozyme (Lyz) and ubiquitin (Ub), was studied with ESI-MS (ElectroSpray Ionization-Mass Spectroscopy), EPR (Electron Paramagnetic Resonance), and computational (docking) techniques. It was shown that, in the metal concentration range close to that found in the organism (15-250 µM), V III (acac) 3 is oxidized to V IV O(acac) + and V IV O(acac) 2 , which-in their turn-interact with proteins to give n[V IV O(acac)]-Protein and n[V IV O(acac) 2 ]-Protein adducts. Similarly, the complex in the +IV oxidation state, V IV O(acac) 2 , dissociates to the mono-chelated species V IV O(acac) + which binds to Lyz and Ub. Finally, V V O 2 (acac) − 2 undergoes complete dissociation to give the 'bare' V V O + 2 ion that forms adducts n[V V O 2 ]-Protein with n = 1-3. Docking calculations allowed the prediction of the residues involved in the metal binding. The results suggest that only the V IV O complex of acetylacetonate survives in the presence of proteins and that its adducts could be the species responsible of the observed pharmacological activity, suggesting that in these systems V IV O 2+ ion should be used in the design of potential vanadium drugs. If V III or V V O 2 potential active complexes had to be designed, the features of the organic ligand must be adequately modulated to obtain species with high redox and thermodynamic stability to prevent oxidation and dissociation.

show abstract

“…Others, like those we recently developed inside the GOLD framework, stand on introducing some directionality to the vacant sites of the metal by explicitly simulating coordination bonds but are still restricted in terms of first coordination sphere description. 16 Indeed, the user needs to define how the metal–protein interaction should take place in terms of angle and direction.…”

Section: Introductionmentioning

confidence: 99%

Simple Coordination Geometry Descriptors Allow to Accurately Predict Metal-Binding Sites in Proteins

et al. 2019

Self Cite

View full text Add to dashboard Cite

With more than a third of the genome encoding for metal-containing biomolecules, the in silico prediction of how metal ions bind to proteins is crucial in chemistry, biology, and medicine. To date, algorithms for metal-binding site prediction are mainly based on sequence analysis. Those methods have reached enough quality to predict the correct region of the protein and the coordinating residues involved in metal-binding, but they do not provide three-dimensional (3D) models. On the contrary, the prediction of accurate 3D models for protein–metal adducts by structural bioinformatics and molecular modeling techniques is still a challenge. Here, we present an update of our multipurpose molecular modeling suite, GaudiMM, to locate metal-binding sites in proteins. The approach is benchmarked on 105 X-ray structures with resolution lower than 2.0 Å. Results predict the correct binding site of the metal in the biological scaffold for all the entries in the data set. Generated 3D models of the protein–metal coordination complexes reach root-mean-square deviation values under 1.0 Å between calculated and experimental structures. The whole process is purely based on finding poses that satisfy metal-derived geometrical rules without needing sequence or fine electronic inputs. Additional post-optimizations, including receptor flexibility, have been tested and suggest that more extensive searches, required when the host structures present a low level of pre-organization, are also possible. With this new update, GaudiMM is now able to look for metal-binding sites in biological scaffolds and clearly shows how explicitly considering the geometric particularities of the first coordination sphere of the metal in a docking process provides excellent results.

show abstract

Elucidation of Binding Site and Chiral Specificity of Oxidovanadium Drugs with Lysozyme through Theoretical Calculations

Cited by 44 publications

References 93 publications

Prediction of the interaction of metallic moieties with proteins: An update for protein‐ligand docking techniques

Prediction of the interaction of metallic moieties with proteins: An update for protein‐ligand docking techniques

Biospeciation of Potential Vanadium Drugs of Acetylacetonate in the Presence of Proteins

Simple Coordination Geometry Descriptors Allow to Accurately Predict Metal-Binding Sites in Proteins

Contact Info

Product

Resources

About