Molecules

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28 pages, 17235 KiB

Open AccessArticle

Combination of Hydrogen and Halogen Bonds in the Crystal Structures of 5-Halogeno-1H-isatin-3-oximes: Involvement of the Oxime Functionality in Halogen Bonding

by Eric Meier, Wilhelm Seichter and Monika Mazik

Molecules 2024, 29(5), 1174; https://doi.org/10.3390/molecules29051174 - 6 Mar 2024

Cited by 1 | Viewed by 1046

Abstract

Various functional groups have been considered as acceptors for halogen bonds, but the oxime functionality has received very little attention in this context. In this study, we focus on the analysis of the hydrogen and halogen bond preferences observed in the crystal structures [...] Read more.

Various functional groups have been considered as acceptors for halogen bonds, but the oxime functionality has received very little attention in this context. In this study, we focus on the analysis of the hydrogen and halogen bond preferences observed in the crystal structures of 5-halogeno-1H-isatin-3-oximes. These molecules can be involved in various non-covalent interactions, and the competition between these interactions has a decisive influence on their self-organization. In particular, we were interested to see whether the crystal structures of 5-halogeno-1H-isatin-3-oximes, especially bromine- and iodine-substituted ones, are characterized by the presence of halogen bonds formed with the oxime functionality. The oxime group proved its ability to compete with the other strong donor and acceptor sites by participating in the formation of cyclic hydrogen-bonded heterosynthons oxime∙∙∙amide and O_oxime∙∙∙Br/I halogen bonds. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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22 pages, 3586 KiB

Open AccessArticle

An Assessment of Dispersion-Corrected DFT Methods for Modeling Nonbonded Interactions in Protein Kinase Inhibitor Complexes

by Yan Zhu, Saad Alqahtani and Xiche Hu

Molecules 2024, 29(2), 304; https://doi.org/10.3390/molecules29020304 - 6 Jan 2024

Viewed by 1702

Abstract

Accurate modeling of nonbonded interactions between protein kinases and their small molecule inhibitors is essential for structure-based drug design. Quantum chemical methods such as density functional theory (DFT) hold significant promise for quantifying the strengths of these key protein–ligand interactions. However, the accuracy [...] Read more.

Accurate modeling of nonbonded interactions between protein kinases and their small molecule inhibitors is essential for structure-based drug design. Quantum chemical methods such as density functional theory (DFT) hold significant promise for quantifying the strengths of these key protein–ligand interactions. However, the accuracy of DFT methods can vary substantially depending on the choice of exchange–correlation functionals and associated basis sets. In this study, a comprehensive benchmarking of nine widely used DFT methods was carried out to identify an optimal approach for quantitative modeling of nonbonded interactions, balancing both accuracy and computational efficiency. From a database of 2139 kinase-inhibitor crystal structures, a diverse library of 49 nonbonded interaction motifs was extracted, encompassing CH–π, π–π stacking, cation–π, hydrogen bonding, and salt bridge interactions. The strengths of nonbonded interaction energies for all 49 motifs were calculated at the advanced CCSD(T)/CBS level of theory, which serve as references for a systematic benchmarking of BLYP, TPSS, B97, ωB97X, B3LYP, M062X, PW6B95, B2PLYP, and PWPB95 functionals with D3BJ dispersion correction alongside def2-SVP, def2-TZVP, and def2-QZVP basis sets. The RI, RIJK, and RIJCOSX approximations were used for selected functionals. It was found that the B3LYP/def2-TZVP and RIJK RI-B2PLYP/def2-QZVP methods delivered the best combination of accuracy and computational efficiency, making them well-suited for efficient modeling of nonbonded interactions responsible for molecular recognition of protein kinase inhibitors in their targets. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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12 pages, 3160 KiB

Open AccessArticle

The Structure of 2,6-Di-tert-butylphenol–Argon by Rotational Spectroscopy

by Wenqin Li, Assimo Maris, Sonia Melandri, Alberto Lesarri and Luca Evangelisti

Molecules 2023, 28(24), 8111; https://doi.org/10.3390/molecules28248111 - 15 Dec 2023

Cited by 3 | Viewed by 1116

Abstract

The molecular structure of a van der Waals-bonded complex involving 2,6-di-tert-butylphenol and a single argon atom has been determined through rotational spectroscopy. The experimentally derived structural parameters were compared to the outcomes of quantum chemical calculations that can accurately account for dispersive interactions [...] Read more.

The molecular structure of a van der Waals-bonded complex involving 2,6-di-tert-butylphenol and a single argon atom has been determined through rotational spectroscopy. The experimentally derived structural parameters were compared to the outcomes of quantum chemical calculations that can accurately account for dispersive interactions in the cluster. The findings revealed a π-bound configuration for the complex, with the argon atom engaging the aromatic ring. The microwave spectrum reveals both fine and hyperfine tunneling components. The main spectral doubling is evident as two distinct clusters of lines, with an approximate separation of 179 MHz, attributed to the torsional motion associated with the hydroxyl group. Additionally, each component of this doublet further splits into three components, each with separations measuring less than 1 MHz. Investigation into intramolecular dynamics using a one-dimensional flexible model suggests that the main tunneling phenomenon originates from equivalent positions of the hydroxyl group. A double-minimum potential function with a barrier of 1000 (100) cm⁻¹ effectively describes this extensive amplitude motion. However, the three-fold fine structure, potentially linked to internal motions within the tert-butyl group, requires additional scrutiny for a comprehensive understanding. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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17 pages, 2488 KiB

Open AccessArticle

Intermolecular Non-Bonded Interactions from Machine Learning Datasets

by Jia-An Chen and Sheng D. Chao

Molecules 2023, 28(23), 7900; https://doi.org/10.3390/molecules28237900 - 1 Dec 2023

Cited by 3 | Viewed by 1530

Abstract

Accurate determination of intermolecular non-covalent-bonded or non-bonded interactions is the key to potentially useful molecular dynamics simulations of polymer systems. However, it is challenging to balance both the accuracy and computational cost in force field modelling. One of the main difficulties is properly [...] Read more.

Accurate determination of intermolecular non-covalent-bonded or non-bonded interactions is the key to potentially useful molecular dynamics simulations of polymer systems. However, it is challenging to balance both the accuracy and computational cost in force field modelling. One of the main difficulties is properly representing the calculated energy data as a continuous force function. In this paper, we employ well-developed machine learning techniques to construct a general purpose intermolecular non-bonded interaction force field for organic polymers. The original ab initio dataset SOFG-31 was calculated by us and has been well documented, and here we use it as our training set. The CLIFF kernel type machine learning scheme is used for predicting the interaction energies of heterodimers selected from the SOFG-31 dataset. Our test results show that the overall errors are well below the chemical accuracy of about 1 kcal/mol, thus demonstrating the promising feasibility of machine learning techniques in force field modelling. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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26 pages, 46902 KiB

Open AccessArticle

Repurposing Drugs for Inhibition against ALDH2 via a 2D/3D Ligand-Based Similarity Search and Molecular Simulation

by Wanyun Jiang, Junzhao Chen, Puyu Zhang, Nannan Zheng, Le Ma, Yongguang Zhang and Haiyang Zhang

Molecules 2023, 28(21), 7325; https://doi.org/10.3390/molecules28217325 - 29 Oct 2023

Cited by 1 | Viewed by 1651

Abstract

Aldehyde dehydrogenase-2 (ALDH2) is a crucial enzyme participating in intracellular aldehyde metabolism and is acknowledged as a potential therapeutic target for the treatment of alcohol use disorder and other addictive behaviors. Using previously reported ALDH2 inhibitors of Daidzin, CVT-10216, and CHEMBL114083 as reference [...] Read more.

Aldehyde dehydrogenase-2 (ALDH2) is a crucial enzyme participating in intracellular aldehyde metabolism and is acknowledged as a potential therapeutic target for the treatment of alcohol use disorder and other addictive behaviors. Using previously reported ALDH2 inhibitors of Daidzin, CVT-10216, and CHEMBL114083 as reference molecules, here we perform a ligand-based virtual screening of world-approved drugs via 2D/3D similarity search methods, followed by the assessments of molecular docking, toxicity prediction, molecular simulation, and the molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) analysis. The 2D molecular fingerprinting of ECFP4 and FCFP4 and 3D molecule-shape-based USRCAT methods show good performances in selecting compounds with a strong binding behavior with ALDH2. Three compounds of Zeaxanthin (q = 0), Troglitazone (q = 0), and Sequinavir (q = +1 e) are singled out as potential inhibitors; Zeaxanthin can only be hit via USRCAT. These drugs displayed a stronger binding strength compared to the reported potent inhibitor CVT-10216. Sarizotan (q = +1 e) and Netarsudil (q = 0/+1 e) displayed a strong binding strength with ALDH2 as well, whereas they displayed a shallow penetration into the substrate-binding tunnel of ALDH2 and could not fully occupy it. This likely left a space for substrate binding, and thus they were not ideal inhibitors. The MM–PBSA results indicate that the selected negatively charged compounds from the similarity search and Vina scoring are thermodynamically unfavorable, mainly due to electrostatic repulsion with the receptor (q = −6 e for ALDH2). The electrostatic attraction with positively charged compounds, however, yielded very strong binding results with ALDH2. These findings reveal a deficiency in the modeling of electrostatic interactions (in particular, between charged moieties) in the virtual screening via the 2D/3D similarity search and molecular docking with the Vina scoring system. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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14 pages, 2675 KiB

Open AccessArticle

Extending the Affinity Range of Weak Affinity Chromatography for the Identification of Weak Ligands Targeting Membrane Proteins

by Adrien Deloche, François-Xavier Vidal, Lucile Jammas, Renaud Wagner, Vincent Dugas and Claire Demesmay

Molecules 2023, 28(20), 7113; https://doi.org/10.3390/molecules28207113 - 16 Oct 2023

Viewed by 1691

Abstract

The identification of weak-affinity ligands targeting membrane proteins is of great interest in Fragment-Based Drug Design (FBDD). Recently, miniaturized weak affinity chromatography (WAC) has been proposed as a valuable tool to study interactions between small ligands and wild-type membrane proteins embedded in so-called [...] Read more.

The identification of weak-affinity ligands targeting membrane proteins is of great interest in Fragment-Based Drug Design (FBDD). Recently, miniaturized weak affinity chromatography (WAC) has been proposed as a valuable tool to study interactions between small ligands and wild-type membrane proteins embedded in so-called nanodisc biomimetic membranes immobilized on GMA-co-EDMA monoliths in situ-synthesized in capillary columns (less than one microliter in volume). In this proof-of-concept study, the achievable affinity range was limited to medium affinity (low micromolar range). The present work investigates different strategies to extend the affinity range towards low affinities, either by increasing the density of membrane proteins on the chromatographic support or by reducing non-specific interactions with the monolith. The combination of the use of a new and more hydrophilic monolithic support (poly(DHPMA-co-MBA)) and a multilayer nanodisc grafting process (up to three layers) allows a significant increase in the membrane protein density by a more than three-fold factor (up to 5.4 pmol cm⁻¹). Such an increase in protein density associated with reduced non-specific interactions makes it possible to extend the range of detectable affinity, as demonstrated by the identification and characterization of affinities of very low-affinity ligands (Kd values of several hundred micromolar) for the adenosine receptor AA_2AR used as a model protein, which was not possible before. The affinity was confirmed by competition experiments. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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13 pages, 7704 KiB

Open AccessArticle

Solvent-Induced Lag Phase during the Formation of Lysozyme Amyloid Fibrils Triggered by Sodium Dodecyl Sulfate: Biophysical Experimental and In Silico Study of Solvent Effects

by Gabriel Zazeri, Ana Paula Ribeiro Povinelli, Nathália Mariana Pavan, Alan M. Jones and Valdecir Farias Ximenes

Molecules 2023, 28(19), 6891; https://doi.org/10.3390/molecules28196891 - 30 Sep 2023

Cited by 4 | Viewed by 1428

Abstract

Amyloid aggregates arise from either the partial or complete loss of the native protein structure or the inability of proteins to attain their native conformation. These aggregates have been linked to several diseases, including Alzheimer’s, Parkinson’s, and lysozyme amyloidosis. A comprehensive dataset was [...] Read more.

Amyloid aggregates arise from either the partial or complete loss of the native protein structure or the inability of proteins to attain their native conformation. These aggregates have been linked to several diseases, including Alzheimer’s, Parkinson’s, and lysozyme amyloidosis. A comprehensive dataset was recently reported, demonstrating the critical role of the protein’s surrounding environment in amyloid formation. In this study, we investigated the formation of lysozyme amyloid fibrils induced by sodium dodecyl sulfate (SDS) and the effect of solvents in the medium. Experimental data obtained through fluorescence spectroscopy revealed a notable lag phase in amyloid formation when acetone solution was present. This finding suggested that the presence of acetone in the reaction medium created an unfavorable microenvironment for amyloid fibril formation and impeded the organization of the denatured protein into the fibril form. The in silico data provided insights into the molecular mechanism of the interaction between acetone molecules and the lysozyme protofibril, once acetone presented the best experimental results. It was observed that the lysozyme protofibril became highly unstable in the presence of acetone, leading to the complete loss of its β-sheet conformation and resulting in an open structure. Furthermore, the solvation layer of the protofibril in acetone solution was significantly reduced compared to that in other solvents, resulting in fewer hydrogen bonds. Consequently, the presence of acetone facilitated the exposure of the hydrophobic portion of the protofibril, precluding the amyloid fibril formation. In summary, our study underscores the pivotal role the surrounding environment plays in influencing amyloid formation. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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13 pages, 2660 KiB

Open AccessArticle

Designing Nonconventional Luminescent Materials with Efficient Emission in Dilute Solutions via Modulation of Dynamic Hydrogen Bonds

by Xuansi Tang, Bingli Jiang, Yongyang Gong, Yuxin Jin, Jiao He, Huihong Xie, Song Guo and Yuanli Liu

Molecules 2023, 28(13), 5240; https://doi.org/10.3390/molecules28135240 - 6 Jul 2023

Cited by 2 | Viewed by 1605

Abstract

Nonconventional luminescent materials (NLMs) which do not contain traditional aromatic chromophores are of great interest due to their unique chemical structures, optical properties, and their potential applications in various areas, such as cellular imaging and chemical sensing. However, most reported NLMs show weak [...] Read more.

Nonconventional luminescent materials (NLMs) which do not contain traditional aromatic chromophores are of great interest due to their unique chemical structures, optical properties, and their potential applications in various areas, such as cellular imaging and chemical sensing. However, most reported NLMs show weak or no emission in dilute solutions, which severely limits their applications. In this work, dynamic hydrogen bonds were utilized to design NLMs with efficient emission in dilute solutions. To further validate the results, polymers P1 and P2 were successfully prepared and investigated. It was found that the luminescence quantum efficiency of P1 and P2 at a concentration of 0.1 mg/mL in water solution was 8.9 and 0.6%, respectively. The high efficiency can be attributed to the fact that polymer P1 has more intra- or intermolecular dynamic hydrogen bonds and other short interactions than P2 in dilute solutions, allowing P1 to achieve the through-space conjugation effect to increase the degree of system conjugation, restrict molecular motion, and decrease nonradiative transitions, which can effectively improve luminescence. In addition, polymer P2 exhibits the characteristics of clustering-triggered emission, excitation wavelength-dependent and concentration-dependent fluorescence properties, excellent photobleaching resistance, low cytotoxicity, and selective recognition of Fe³⁺. The present study investigates the manipulation of luminescence properties of NLMs in dilute solutions through the modulation of dynamic hydrogen bonds. This approach can serve as a semi-empirical technique for designing and building innovative NLMs in the times ahead. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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13 pages, 4267 KiB

Open AccessArticle

Rational Engineering of (S)-Norcoclaurine Synthase for Efficient Benzylisoquinoline Alkaloids Biosynthesis

by João P. M. De Sousa, Nuno C. S. A. Oliveira and Pedro A. Fernandes

Molecules 2023, 28(11), 4265; https://doi.org/10.3390/molecules28114265 - 23 May 2023

Cited by 3 | Viewed by 2262

Abstract

(S)-Norcoclaurine is synthesized in vivo through a metabolic pathway that ends with (S)-norcoclaurine synthase (NCS). The former constitutes the scaffold for the biosynthesis of all benzylisoquinoline alkaloids (BIAs), including many drugs such as the opiates morphine and codeine and [...] Read more.

(S)-Norcoclaurine is synthesized in vivo through a metabolic pathway that ends with (S)-norcoclaurine synthase (NCS). The former constitutes the scaffold for the biosynthesis of all benzylisoquinoline alkaloids (BIAs), including many drugs such as the opiates morphine and codeine and the semi-synthetic opioids oxycodone, hydrocodone, and hydromorphone. Unfortunately, the only source of complex BIAs is the opium poppy, leaving the drug supply dependent on poppy crops. Therefore, the bioproduction of (S)-norcoclaurine in heterologous hosts, such as bacteria or yeast, is an intense area of research nowadays. The efficiency of (S)-norcoclaurine biosynthesis is strongly dependent on the catalytic efficiency of NCS. Therefore, we identified vital NCS rate-enhancing mutations through the rational transition-state macrodipole stabilization method at the Quantum Mechanics/Molecular Mechanics (QM/MM) level. The results are a step forward for obtaining NCS variants able to biosynthesize (S)-norcoclaurine on a large scale. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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18 pages, 3119 KiB

Open AccessArticle

A Buckycatcher in Solution—A Computational Perspective

by Filipe Menezes and Grzegorz M. Popowicz

Molecules 2023, 28(6), 2841; https://doi.org/10.3390/molecules28062841 - 21 Mar 2023

Cited by 1 | Viewed by 1305

Abstract

In this work, we study the buckycatcher (C₆₀H₂₈) in solution using quantum chemical models. We investigate the conformational equilibria in several media and the effects that molecules of solvent might have in interconversion barriers between the different conformers. These [...] Read more.

In this work, we study the buckycatcher (C₆₀H₂₈) in solution using quantum chemical models. We investigate the conformational equilibria in several media and the effects that molecules of solvent might have in interconversion barriers between the different conformers. These are studied in a hypothetical gas phase, in the dielectric of a solvent, as well as with hybrid solvation. In the latter case, due to a disruption of π-stacking interactions, the transition states are destabilized. We also evaluate the complexation of the buckycatcher with solvent-like molecules. In most cases studied, there should be no adducts formed because the enthalpy driving force cannot overcome entropic penalties. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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15 pages, 2676 KiB

Open AccessArticle

A Theoretical Analysis of Interaction Energies and Intermolecular Interactions between Amphotericin B and Potential Bioconjugates Used in the Modification of Nanocarriers for Drug Delivery

by Jennifer Cuellar, Lorena Parada-Díaz, Jorge Garza and Sol M. Mejía

Molecules 2023, 28(6), 2674; https://doi.org/10.3390/molecules28062674 - 15 Mar 2023

Cited by 5 | Viewed by 2197

Abstract

Amphotericin B (AmB) is an antibiotic with a wide spectrum of action and low multidrug resistance, although it exhibits self-aggregation, low specificity, and solubility in aqueous media. An alternative for its oral administration is its encapsulation in polymers modified with bioconjugates. The aim [...] Read more.

Amphotericin B (AmB) is an antibiotic with a wide spectrum of action and low multidrug resistance, although it exhibits self-aggregation, low specificity, and solubility in aqueous media. An alternative for its oral administration is its encapsulation in polymers modified with bioconjugates. The aim of the present computational research is to determine the affinity between AmB and six bioconjugates to define which one could be more suitable. The CAM-B3LYP-D3/6-31+G(d,p) method was used for all computational calculations. The dimerization enthalpy of the most stable and abundant systems at pH = 7 allows obtaining this affinity order: AmB_1,2-distearoyl-sn-glycerol-3-phosphorylethanolamine (DSPE) > AmB_γ-cyclodextrin > AmB_DSPEc > AmB_retinol > AmB_cholesterol > AmB_dodecanol, where DSPEc is a DSPE analog. Quantum theory of atoms in molecules, the non-covalent interactions index, and natural bond orbital analysis revealed the highest abundance of noncovalent interactions for AmB-DSPE (51), about twice the number of interactions of the other dimers. Depending on the interactions’ strength and abundance of the AmB-DSPE dimer, these are classified as strong: O-H---O (2), N-H---O (3) and weak: C-H---O (25), H---H (18), C-H---C (3). Although the C-H---O hydrogen bond is weak, the number of interactions involved in all dimers cannot be underestimated. Thus, non-covalent interactions drive the stabilization of copolymers, and from our analysis, the most promising candidates for encapsulating are DSPE and γ-cyclodextrin. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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12 pages, 1938 KiB

Open AccessArticle

Influence of β-Cyclodextrin Methylation on Host-Guest Complex Stability: A Theoretical Study of Intra- and Intermolecular Interactions as Well as Host Dimer Formation

by Niklas Geue, Jackson J. Alcázar and Paola R. Campodónico

Molecules 2023, 28(6), 2625; https://doi.org/10.3390/molecules28062625 - 14 Mar 2023

Cited by 6 | Viewed by 2570

Abstract

Understanding the non-covalent interactions in host-guest complexes is crucial to their stability, design and applications. Here, we use density functional theory to compare the ability of β-cyclodextrin (β-CD) and heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) to encapsulate the model guest phenol. For both [...] Read more.

Understanding the non-covalent interactions in host-guest complexes is crucial to their stability, design and applications. Here, we use density functional theory to compare the ability of β-cyclodextrin (β-CD) and heptakis(2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) to encapsulate the model guest phenol. For both macrocycles, we quantify the intramolecular interactions before and after the formation of the complex, as well as the intermolecular host-guest and host-host dimer interactions. These are individually classified as van der Waals interactions or hydrogen bonds, respectively. The results show a stronger intramolecular binding energy of β-CD, with the absolute difference being −5.53 kcal/mol relative to DM-β-CD. Consequently, the intermolecular interactions of both cyclodextrins with phenol are affected, such that the free binding energy calculated for the DM-β-CD/phenol complex (−5.23 kcal/mol) is ≈50% more negative than for the complex with β-CD (−2.62 kcal/mol). The latter is in excellent agreement with the experimental data (−2.69 kcal/mol), which validates the level of theory (B97-3c) used. Taken together, the methylation of β-CD increases the stability of the host-guest complex with the here studied guest phenol through stronger van der Waals interactions and hydrogen bonds. We attribute this to the disruption of the hydrogen bond network in the primary face of β-CD upon methylation, which influences the flexibility of the host toward the guest as well as the strength of the intermolecular interactions. Our work provides fundamental insights into the impact of different non-covalent interactions on host-guest stability, and we suggest that this theoretical framework can be adapted to other host-guest complexes to evaluate and quantify their non-covalent interactions. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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14 pages, 5814 KiB

Open AccessArticle

Computational Studies of Auto-Active van der Waals Interaction Molecules on Ultra-Thin Black-Phosphorus Film

by Slimane Laref, Bin Wang, Xin Gao and Takashi Gojobori

Molecules 2023, 28(2), 681; https://doi.org/10.3390/molecules28020681 - 9 Jan 2023

Cited by 6 | Viewed by 2010

Abstract

Using the van der Waals density functional theory, we studied the binding peculiarities of favipiravir (FP) and ebselen (EB) molecules on a monolayer of black phosphorene (BP). We systematically examined the interaction characteristics and thermodynamic properties in a vacuum and a continuum, solvent [...] Read more.

Using the van der Waals density functional theory, we studied the binding peculiarities of favipiravir (FP) and ebselen (EB) molecules on a monolayer of black phosphorene (BP). We systematically examined the interaction characteristics and thermodynamic properties in a vacuum and a continuum, solvent interface for active drug therapy. These results illustrate that the hybrid molecules are enabled functionalized two-dimensional (2D) complex systems with a vigorous thermostability. We demonstrate in this study that these molecules remain flat on the monolayer BP system and phosphorus atoms are intact. It is inferred that the hybrid FP+EB molecules show larger adsorption energy due to the van der Waals forces and planar electrostatic interactions. The changes in Gibbs free energy at different surface charge fluctuations and temperatures imply that the FP and EB are allowed to adsorb from the gas phase onto the 2D film at high temperatures. Thereby, the results unveiled beneficial inhibitor molecules on two dimensional BP nanocarriers, potentially introducing a modern strategy to enhance the development of advanced materials, biotechnology, and nanomedicine. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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15 pages, 1725 KiB

Open AccessArticle

Computer- and NMR-Aided Design of Small-Molecule Inhibitors of the Hub1 Protein

by Atilio Reyes Romero, Katarzyna Kubica, Radoslaw Kitel, Ismael Rodríguez, Katarzyna Magiera-Mularz, Alexander Dömling, Tad A. Holak and Ewa Surmiak

Molecules 2022, 27(23), 8282; https://doi.org/10.3390/molecules27238282 - 28 Nov 2022

Cited by 1 | Viewed by 1882 | Correction

Abstract

By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked [...] Read more.

By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to several human pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, and cancer. To identify small molecule ligands for Hub1, we used the interface analysis, peptide modeling of the Hub1/Snu66 interaction and the fragment-based NMR screening. Fragment-based NMR screening has not proven sufficient to unambiguously search for fragments that bind to the Hub1 protein. This was because the Snu66 binding pocket of Hub1 is occupied by pH-sensitive residues, making it difficult to distinguish between pH-induced NMR shifts and actual binding events. The NMR analyses were therefore verified experimentally by microscale thermophoresis and by NMR pH titration experiments. Our study found two small peptides that showed binding to Hub1. These peptides are the first small-molecule ligands reported to interact with the Hub1 protein. Full article

(This article belongs to the Special Issue Exploring Non-bonded Interactions in Macromolecular Chemistry)

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