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Exploring Molecular Properties Through Molecular Modeling

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Informatics".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 4234

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Prof. Dr. Emili Besalu

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Institut de Química Computacional i Catàlisi (IQCC), Departament de Química, Universitat de Girona, 17071 Girona, Spain
Interests: the QSAR field of molecular property prediction; new mathematical methods; chemometric algorithms; quantitative structure-activity relationships (QSAR); quantitative structure-property relationships (QSPR); quantum chemistry;

Special Issue Information

Dear Colleagues,

One of the most promising fields in modern chemistry is molecular modeling. The concept is broad and has a significant impact on many areas, such as drug design, materials science, and biological modeling, among others. Furthermore, its applicability ranges from small-scale systems to large biological environments. In short, the main advantages of molecular modeling have been gradually proven: from the basic description of molecules, physicochemical properties can be designed, and, even more importantly, sophisticated structure–activity relationships can be predicted and interpreted. Modern and successful molecular modeling technologies exhibit the powerful ability to predict property values before chemical synthesis. This Special Issue is dedicated to presenting the state of the art in molecular modeling, showcasing both the variety of modern techniques that drive the methodology and the range of useful results that can be achieved.

Prof. Dr. Emili Besalu
Guest Editor

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Keywords

molecular modeling
molecular properties
structure–activity relationships
QSAR
prediction
drug design
materials science
virtual screening
in-silico synthesis
computational chemistry
cheminformatics

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Published Papers (6 papers)

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Research

17 pages, 1493 KB

Open AccessArticle

In Silico Prioritisation of Similarity-Selected Small Molecules Targeting the IsdB NEAT Domain of Staphylococcus aureus as a Potential Antivirulence Strategy

by Warinda Prommachote, Manu Deeudom, Hridek Manimaran, Jittasak Khowsathit, Pimpisid Koonyosying, Bishant Pokharel, Yuvaraj Ravikumar and Somdet Srichairatanakool

Int. J. Mol. Sci. 2026, 27(13), 5834; https://doi.org/10.3390/ijms27135834 - 28 Jun 2026

Viewed by 229

Abstract

The increasing prevalence of multidrug-resistant Staphylococcus aureus (MRSA) has necessitated the development of alternative therapeutic strategies targeting bacterial virulence factors. This study employed an integrated in silico approach to identifying potential inhibitors of the iron-regulated surface determinant B Near-iron Transporter domain, a key protein involved in heme acquisition and pathogenicity. Virtual screening and molecular docking identified certain similarity-selected small molecules possessing strong binding affinities, with (4-(1-oxoisoindolin-2-yl)benzoic acid (TOP1) and (4-(2-oxochromen-3-yl)benzoic acid (TOP2) exhibiting the most favorable binding energies at −12.0 and −11.8 kcal/mol, respectively. Molecular dynamics simulations over 200 ns confirmed stable protein–ligand interactions that yielded reduced structural fluctuations in ligand-bound complexes when compared with the apo form. Molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) analysis revealed that van der Waals interactions were the primary contributors to binding, with TOP1 showing a more favorable overall binding energy. Drug-likeness and pharmacokinetic predictions indicated compliance with Lipinski’s rule of five and moderate bioavailability, although limited intestinal absorption was observed. Toxicity predictions indicated that both compounds are non-mutagenic but may exhibit hepatotoxicity. Notably, TOP1 exhibited potential nephrotoxicity, cardiotoxicity, and carcinogenicity, whereas TOP2 demonstrated a more favorable safety profile. These findings highlight a trade-off between binding affinity and safety, suggesting that TOP2 emerged as a computationally prioritized candidate for future experimental validation. Because the present findings represent computational predictions only, further orthogonal computational analyses and experimental studies are required to confirm the proposed binding modes, biological activity, and therapeutic potential of the identified compounds. Full article

(This article belongs to the Special Issue Exploring Molecular Properties Through Molecular Modeling)

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21 pages, 3894 KB

Open AccessArticle

Molecular Mechanisms of Interaction of Human Serum Albumin with the CD36 Receptor: Insights from Molecular Dynamics Simulations

by Daria A. Belinskaia, Richard O. Jenkins and Nikolay V. Goncharov

Int. J. Mol. Sci. 2026, 27(12), 5395; https://doi.org/10.3390/ijms27125395 - 15 Jun 2026

Viewed by 402

Abstract

The rate of fatty acid (FA) uptake by cells depends on the presence of the CD36 receptor on the cell surface. However, unesterified FAs cannot circulate freely in plasma; they are bound to serum albumin. The molecular mechanisms of FA transfer from albumin to CD36 remain poorly understood. This study used macromolecular docking and molecular dynamics methods to investigate the interaction of the CD36 receptor with human serum albumin (HSA) loaded with oleic acid at the FA1-7 fatty acid-binding sites, with the aim of identifying potential mechanisms of FA transfer from HSA to CD36. The data obtained indicate that the interaction of HSA with CD36 does not result in direct FA transfer, but rather causes a local weakening of the affinity of individual FA sites on HSA. A comparative analysis was performed between the interaction interfaces predicted by macromolecular docking and those generated by AlphaFold 3. To further evaluate the influence of ligand nature, an additional molecular docking of HSA loaded with saturated (palmitic, PALM) and polyunsaturated (arachidonic, ARA) acids to the CD36 receptor was performed. This revealed a marked sensitivity of the protein–protein interface architecture to the type of lipid ligand, with the effect of ARA being more pronounced than PALM. Conversely, an alternative structure prediction using the AlphaFold3 algorithm demonstrated the opposite trend, indicating high geometric invariance and reproducibility of the complex. Ultimately, the proposed dynamic mechanism expands our understanding of the multi-stage processes governing FA transport across the endothelium. Full article

(This article belongs to the Special Issue Exploring Molecular Properties Through Molecular Modeling)

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26 pages, 5281 KB

Open AccessArticle

Chemical Composition, Antioxidant, and Anti-Inflammatory Activity of the Antarctic Lichen Leptogium puberulum: A Combination of Metabolomic, In Vitro, and In Silico Approaches

by Alfredo Torres-Benítez, José Erick Ortega-Valencia, Juan Rodrigo Salazar, Katherine Monje, Jaqueline Ley-Martínez, Gabriel Vargas-Arana and Mario J. Simirgiotis

Int. J. Mol. Sci. 2026, 27(11), 4822; https://doi.org/10.3390/ijms27114822 - 27 May 2026

Viewed by 393

Abstract

Lichenized fungi are a source of secondary metabolites with multiple biological potential. The objective of the study was to determine the chemical composition, antioxidant, and anti-inflammatory activity of the hydroalcoholic extract of the Antarctic lichen Leptogium puberulum through metabolomic, in vitro, and in silico analyses. Seventeen compounds were tentatively identified using UHPLC-ESI-QToF-MS. The phenolic composition yielded 6.356 mg GAE/g, and antioxidant activity assays showed IC₅₀ values for DPPH• and ABTS•⁺ of 1187.149 and 207.00 µg/mL, respectively, along with 15.845 µmol Trolox/g for ORAC and 21.925 µmol Trolox/g for FRAP. The in silico evaluation was performed using OSIRIS Data Warrior, ProTox 3.0, and SwissTargetPrediction, identifying 9,10,12,13,14-pentahydroxytetracosanoic acid (PHTA), 9,10,12,13-tetrahydroxytricosanoic acid (THTA), 9,10,12,13-tetrahydroxyheneicosanoic acid (THHA), and 9,10,12,13-tetrahydroxydocosanoic acid (THDA) as the most promising compounds. These metabolites showed favorable pharmacokinetic properties, with no anticipated toxicological risks. Subsequently, their affinity for the cyclooxygenase-2 (COX-2) enzyme was evaluated by molecular docking with AutoDock Vina software version 1.2.3, and the most stable protein–ligand complexes were analyzed to characterize key interactions within the active site and subjected to molecular dynamics simulations with YASARA software version 19.1.27 for 100 ns. Overall, these results indicate that selected metabolites from L. puberulum may act as potential COX-2 inhibitors, supporting their relevance as lichen-derived anti-inflammatory agents and warranting further pharmacological investigation. Full article

(This article belongs to the Special Issue Exploring Molecular Properties Through Molecular Modeling)

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28 pages, 25686 KB

Open AccessArticle

Binding Affinity and Interaction Profiles of Erinacines and Erinacerins with iNOS and NF-κB Revealed by Molecular Dynamics Simulations

by April Michelle Hernandez-Munguia, Andrés Reyes-Chaparro, Tomas Alejandro Fregoso-Aguilar, Aldo Yair Tenorio-Barajas, Jorge Alberto Mendoza-Pérez, Ricardo Aguilar-Garay and Dulce E. Nicolás-Álvarez

Int. J. Mol. Sci. 2026, 27(7), 3145; https://doi.org/10.3390/ijms27073145 - 30 Mar 2026

Viewed by 1185

Abstract

Chronic neuroinflammation driven by microglial activation is a pathological hallmark of neurodegenerative diseases, and the NF-

κ

B/iNOS signaling axis plays a central role in propagating this damage. NF-

κ

B-mediated iNOS transcription generates excessive nitric oxide, causing oxidative neuronal injury. The medicinal [...] Read more.

Chronic neuroinflammation driven by microglial activation is a pathological hallmark of neurodegenerative diseases, and the NF-

κ

B/iNOS signaling axis plays a central role in propagating this damage. NF-

κ

B-mediated iNOS transcription generates excessive nitric oxide, causing oxidative neuronal injury. The medicinal mushroom Hericium erinaceus produces cyathane diterpenoid erinacines and isoindolinone erinacerins, both reported to attenuate neuroinflammation; however, the molecular basis of their interactions with iNOS and NF-

κ

B remains poorly characterized. We screened 21 erinacerins and 18 erinacines against both targets using validated molecular docking, then subjected top-ranked candidates and negative controls to 100 ns molecular dynamics simulations, MM-PBSA binding free energy calculations (±SEM), per-residue energy decomposition, backbone RMSD, and ligand–protein minimum distance analyses, with quercetin as reference. The analysis revealed scaffold-dependent target selectivity: erinacerins exhibited preferential stability with iNOS (erinacerin L: RMSD 0.185 nm), whereas erinacines formed more stable complexes with NF-

κ

B (erinacines G and J: RMSD < 0.36 nm). Minimum-distance monitoring confirmed that the elevated ligand RMSD in iNOS predominantly reflected surface relocation rather than dissociation. Erinacine S emerged as the most promising dual-target candidate (

Δ G_{b i n d}

: −24.31 ± 0.16 and −14.24 ± 0.11 kcal/mol for iNOS and NF-

κ

B, respectively), over twofold stronger than quercetin for iNOS. Negative controls revealed that docking-based ranking was target-dependent in its discriminative capacity, underscoring the need for MD-based refinement. These results identify erinacine S as a priority candidate for experimental validation. Full article

(This article belongs to the Special Issue Exploring Molecular Properties Through Molecular Modeling)

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12 pages, 2154 KB

Open AccessArticle

In Silico Comparative Analysis of the Plant Growth Regulators Forchlorfenuron (CPPU) and Strigol (STG) Interacting with the Gibberellin Biosynthetic Enzyme GA3Ox2 and the Auxin Signaling Protein Receptor IAA7

by Giovanny Hernández Montaño, Dulce Estefanía Nicolas Álvarez, Silvia Patricia Paredes Carrera, Benjamín Iván Romero De La Rosa and Jorge Alberto Mendoza Pérez

Int. J. Mol. Sci. 2026, 27(7), 2925; https://doi.org/10.3390/ijms27072925 - 24 Mar 2026

Viewed by 531

Abstract

Plant growth regulation is orchestrated by complex hormonal networks involving gibberellin and auxin signaling pathways. In this study, a comprehensive in silico approach was employed to comparatively evaluate the plant growth regulators (PGRs) forchlorfenuron (CPPU) and strigol (STG) against two key proteins from Arabidopsis thaliana: Gibberellin 3-beta-dioxygenase 2 (GA3Ox2), a rate-limiting enzyme in the biosynthesis of bioactive gibberellins, and the auxin signaling repressor IAA7. These targets were specifically selected because they represent critical regulatory nodes in two major hormonal pathways controlling plant growth: GA3Ox2 governs the final steps of gibberellin activation, while IAA7 modulates auxin-responsive gene expression through its interaction with Auxin Response Factors. Therefore, their combined analysis enables the evaluation of potential regulatory effects of PGRs on both gibberellin biosynthesis and auxin-mediated transcriptional control. Molecular docking analyses revealed that both ligands exhibited higher binding affinity toward GA3Ox2 than IAA7, with STG showing slightly more favorable binding energies (−7.91 kcal/mol for GA3Ox2 and −5.43 kcal/mol for IAA7) compared to CPPU (−7.18 and −4.79 kcal/mol, respectively). These results suggest a structural preference of both PGRs toward the gibberellin biosynthetic pathway. To further assess complex stability under near-physiological conditions, 100 ns molecular dynamics (MD) simulations were conducted using the CHARMM36m force field. Despite its slightly lower docking scores, CPPU demonstrated greater conformational stability, lower RMSD fluctuations, and more persistent hydrogen bonding patterns, particularly in complexes with IAA7. In contrast, STG induced more pronounced conformational rearrangements, although it promoted slightly more compact protein conformations in certain systems. Fourier-transform infrared (FTIR) spectroscopy supported the computational findings by confirming the presence of key functional groups responsible for hydrogen bonding and hydrophobic interactions. Collectively, the results indicate that although STG exhibits higher initial binding affinity, CPPU forms more dynamically stable complexes with both proteins. These findings suggest that CPPU may represent a more robust candidate for sustained modulation of auxin and gibberellin signaling pathways in plant growth regulation. Full article

(This article belongs to the Special Issue Exploring Molecular Properties Through Molecular Modeling)

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18 pages, 4065 KB

Open AccessArticle

Enhanced Inhibition of Trametes versicolor by Structurally Modified Medicarpin: In Vitro Evaluation and In Silico Insights into Laccase Binding

by Santiago José Guevara-Martínez, José Domingo Rivera-Ramírez, Rebeca Escutia-Gutiérrez, Marco Antonio Pérez-Cisneros, Francisco Villanueva-Mejía, Stephanie García-Zavala, Rafael Herrera-Bucio and Fredy Geovannini Morales-Palacios

Int. J. Mol. Sci. 2026, 27(6), 2878; https://doi.org/10.3390/ijms27062878 - 22 Mar 2026

Viewed by 839

Abstract

Medicarpin, a natural pterocarpan phytoalexin, contributes to tree defense against microbial decay, particularly from the aggressive white-rot fungus Trametes versicolor, an ASTM standard for wood durability testing. To improve upon the inhibitory effect of medicarpin against this fungus (150 mg/L), eleven derivatives were synthesized and evaluated. The acetylated analog demonstrated superior activity, achieving complete growth inhibition at 100 mg/L. To establish a structure–activity relationship, molecular docking was performed on the copper cluster on fungal laccase, the primary oxidative enzyme of T. versicolor. The acetylated derivative bound the T1 copper site with a more favorable free energy (−8.5 kcal/mol) than the parent compound, exhibiting enhanced stabilizing interactions and a binding pose anchored closer to the trinuclear copper cluster (TNC). These results were corroborated by 80 ns molecular dynamics simulations, confirming complex stability and the persistence of key interactions. This study demonstrates that targeted chemical modification of natural phytoalexins can significantly improve their antifungal potency. The superior performance of the acetylated medicarpin derivative, linked to optimized binding at the laccase active site, establishes a clear structure–activity relationship and highlights the potential of such engineered compounds as leads for next-generation, bio-inspired wood preservatives. Full article

(This article belongs to the Special Issue Exploring Molecular Properties Through Molecular Modeling)

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