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30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Computational and Theoretical Chemistry".

Deadline for manuscript submissions: 30 November 2026 | Viewed by 12462

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Dr. Maxim L. Kuznetsov

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Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Avenue Rovisco Pais, 1049-001 Lisbon, Portugal
Interests: computational chemistry; coordination chemistry; molecular catalysis; oxidation of hydrocarbons; activation of small molecules; reaction mechanism; chemical bond nature; non-covalent interactions; cycloaddition
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Dear Colleagues,

This Special Issue celebrates the 30th anniversary of Molecules, one of the leading forums for the dissemination of high-quality research of broad interest in chemical science. Over the last three decades, Molecules has evolved from a pioneering open access journal in organic and natural product chemistry to a comprehensive platform encompassing all facets of chemistry. It currently plays a pivotal role in advancing our understanding of various chemical systems, fostering innovation across disciplines.

Theoretical and computational methods have emerged as indispensable pillars of modern chemistry, offering profound insights into molecular behavior and facilitating advancements across various domains, including but not restricted to drug discovery, material science, nanotechnology, and reaction mechanisms. These methods provide powerful tools to complement experimental studies, bridging the gap between theory and practice and pushing the boundaries of chemistry.

This Special Issue aims to gather high-quality contributions that reflect the profound impact of theoretical and computational methods in modern chemical science. We hope this it will demonstrate the latest developments in this field and highlight the critical role of computational and theoretical methods in shaping the future of chemistry.

Previously unpublished manuscripts in the field of theoretical and computational chemistry or those employing broadly theoretical or computational methods are welcome in this Special Issue.

Dr. Maxim L. Kuznetsov
Guest Editor

Manuscript Submission Information

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Keywords

computational chemistry
quantum chemistry
density functional theory
molecular design
reaction mechanism
chemical bonding
non-covalent interactions
molecular docking

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Published Papers (11 papers)

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Research

15 pages, 1329 KB

Open AccessArticle

Tuning Supramolecular Structure in Trimethylglycine Cocrystals: Competition Between Hydrogen and Halogen Bonding upon Cl/Br Substitution

by Andrei V. Churakov, Alexander G. Medvedev, Anastasia V. Shishkina, Nikita E. Frolov and Mikhail V. Vener

Molecules 2026, 31(6), 1047; https://doi.org/10.3390/molecules31061047 - 21 Mar 2026

Abstract

Two novel cocrystals of zwitterionic trimethylglycine (TMG) with 2,6-dichlorophenol [TMG•2,6-dichlorophenol] (1:1) and 2,6-dibromophenol [TMG•2,6-dibromophenol] (1:2) are synthesized and structurally characterized using single crystal X-ray diffraction. To estimate the energy of various intermolecular interactions, periodic DFT calculations were performed followed by Bader analysis of the crystalline electron density. TMG molecules form dimers in [TMG•2,6-dichlorophenol] (1:1). Its supramolecular structure is governed by the primary charge-assisted H-bonds (~60 kJ/mol) and supported by C–H∙∙∙O contacts (~12 kJ/mol). Cl/Br substitution introduces a more potent halogen-bonding donor. The Br∙∙∙O⁻ interaction (~10 kJ/mol) is strong enough to reorganize the packing into a catemeric motif. As a result, TMG molecules form infinite chains in [TMG•2,6-dibromophenol] (1:2). This illustrates that “fine tuning” is not merely about changing distances, but about shifting the entire energy hierarchy of the crystal. Two-dimensional fingerprint diagrams (2D diagrams) obtained from the Hirshfeld surface and Bader’s analysis of the crystalline electron density give significantly different values of the contributions of the H∙∙∙H contacts, 28% vs. 5% respectively. The main reason for this discrepancy is the large number of relatively short intermolecular H∙∙∙H contacts without a critical bond point in trimethylglycine cocrystals. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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30 pages, 41628 KB

Open AccessArticle

Molecular Dynamics-Based Calibrated Micromechanics Model for Elastic Properties of Fullerene-PMMA Nanocomposites Incorporating Interface Stress

by Saeid Sahmani, Eligiusz Postek and Tomasz Sadowski

Molecules 2026, 31(6), 944; https://doi.org/10.3390/molecules31060944 - 12 Mar 2026

Viewed by 258

Abstract

Fullerene-based polymer nanocomposites are promising candidates for micro- and nano-electromechanical systems (MEMSs/NEMSs) due to their tunable mechanical performance and high surface-to-volume ratios. At the nanoscale, interfacial stresses strongly influence the effective elastic response, yet quantitative interface parameters are rarely available for continuum modeling. In the current investigation, a molecular dynamics (MD)-based calibrated micromechanics framework is developed to predict the bulk modulus of fullerene-poly(methyl methacrylate) (PMMA) nanocomposites that incorporate interface stress effects. Atomistic representative volume elements (RVEs) containing individual fullerene nanoparticles embedded in a polymer matrix are generated using controlled molecular packing and systematically equilibrated. The bulk moduli of both isolated fullerenes and fullerene-PMMA RVEs are extracted from energy-volume relationships using a Birch-Murnaghan equation of state. These MD results are used to calibrate a size-dependent micromechanics model and to extract the surface Lamé modulus of the polymer-fullerene interface directly. The extracted surface Lamé modulus remains nearly constant (approximately 19 N/m) across all investigated fullerene sizes. In contrast, the interfacial contribution to the effective bulk modulus increases significantly for smaller nanoparticles due to their higher surface to volume ratios. The calibrated model accurately reproduces MD predictions and provides a physically grounded multiscale link between atomistic interfacial behavior and continuum elastic properties. The proposed framework offers a predictive tool for the rational design of surface-dominated nanocomposites in MEMS/NEMS applications. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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26 pages, 4079 KB

Open AccessArticle

Structure-Based Virtual Screening of Plant-Derived Flavonoids as Putative GLUT9 Binders with Antioxidant Properties

by Kevser Kübra Kırboğa, Emre Aktaş, Ecir Uğur Küçüksille and Mithun Rudrapal

Molecules 2026, 31(4), 593; https://doi.org/10.3390/molecules31040593 - 9 Feb 2026

Viewed by 426

Abstract

Hyperuricemia affects approximately 20% of the global adult population and serves as the primary etiological factor for gout. Glucose transporter 9 (GLUT9) plays a critical role in renal urate reabsorption, representing a promising therapeutic target for hyperuricemia treatment. This study employed an integrated computational and experimental approach to identify novel flavonoid-based putative GLUT9 binders, combining molecular docking, molecular dynamics (MD) simulations, ADMET prediction, antioxidant evaluation, and density functional theory (DFT) calculations. Eight structurally diverse flavonoids were docked against the human GLUT9 cryo-EM structure, and antioxidant activities were assessed using DPPH, ABTS, and FRAP assays. All tested flavonoids exhibited favorable binding affinities ranging from −7.67 to −9.10 kcal/mol. Epigallocatechin gallate (EGCG) demonstrated the highest binding affinity (−9.10 kcal/mol) with an extensive hydrogen bonding network, while chrysin exhibited the second-highest affinity (−8.35 kcal/mol) with favorable drug-like properties. MD simulations over 100 ns confirmed the structural stability of the complexes. EGCG displayed exceptional antioxidant capacity (DPPH IC₅₀ = 3.28 μM) superior to ascorbic acid, whereas chrysin showed lower radical scavenging activity despite favorable GLUT9 binding. DFT calculations revealed that higher HOMO energies correlated with enhanced antioxidant activity. These findings suggest that EGCG and chrysin exhibit favorable GLUT9 binding profiles, warranting further functional and pharmacokinetic optimization. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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19 pages, 874 KB

Open AccessArticle

Methods in PES-Learn: Direct-Fit Machine Learning of Born–Oppenheimer Potential Energy Surfaces

by Ian T. Beck, Justin M. Turney and Henry F. Schaefer III

Molecules 2026, 31(1), 100; https://doi.org/10.3390/molecules31010100 - 25 Dec 2025

Viewed by 694

Abstract

The release of PES-Learn version 1.0 as an open-source software package for the automatic construction of machine learning models of semi-global molecular potential energy surfaces (PESs) is presented. Improvements to PES-Learn’s interoperability are stressed with new Python API that simplifies workflows for PES construction via interaction with QCSchema input and output infrastructure. In addition, a new machine learning method is introduced to PES-Learn: kernel ridge regression (KRR). The capabilities of KRR are emphasized with examination of select semi-global PESs. All machine learning methods available in PES-Learn are benchmarked with benzene and ethanol datasets from the rMD17 database to illustrate PES-Learn’s performance ability. Fitting performance and timings are assessed for both systems. Finally, the ability to predict gradients with neural network models is presented and benchmarked with ethanol and benzene. PES-Learn is an active project and welcomes community suggestions and contributions. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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20 pages, 7231 KB

Open AccessArticle

Systematic Exploration of Small-Molecule Binding via a Large Language Model Trained on Textualized Protein–Ligand Interactions

by Taeseob Lee, Heehoon Jung, Ahnjae Jung, JaeWoong Min, Jong Hui Hong, Bin Claire Zhang and Jongsun Jung

Molecules 2025, 30(23), 4516; https://doi.org/10.3390/molecules30234516 - 22 Nov 2025

Viewed by 1136

Abstract

Emergent Large Language Models (LLMs) show impressive capabilities in performing a wide range of tasks. These models can be harnessed for biophysical use as well. The main challenge in this endeavor lies in transforming 3D chemical data into 1D language-like data. We developed a method to transform molecular data into language-like data and tokenize it for LLM use in a biophysical context. We then trained a model and validated it with a known protein–ligand complex. Using the pre-trained result, the model can assess the chemical properties of targets, detect shared binding properties and structures, and reveal related drugs. The model and the synthetic language to describe binding interactions uncovered novel protein–protein networks influenced by ligands, indicating functionally related yet previously unreported interactions. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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15 pages, 7014 KB

Open AccessArticle

Gas Sensing Properties of Pt- and Rh-Decorated InS Monolayer Towards Toxic Industrial Gases: A First-Principles Study

by Jinyan Li, Junxian Lin, Shuying Huang, Dejian Hou, Shaomin Lin and Jianhong Dong

Molecules 2025, 30(23), 4510; https://doi.org/10.3390/molecules30234510 - 22 Nov 2025

Viewed by 401

Abstract

The development of highly sensitive gas sensors for toxic industrial gases (TIGs) is paramount for environmental monitoring and public safety. Here, the first-principles calculations were employed to systematically investigate the potential of Pt- and Rh-decorated InS (Pt-InS and Rh-InS) monolayers as advanced gas sensing materials for the five TIGs (SO₂, NH₃, NO, CO, and NO₂). The results reveal that Pt and Rh atoms can be stably anchored at the InS monolayer, inducing significant modulation of its electronic properties. The Pt-InS system exhibits strong chemisorption of NH₃ and CO, while the other TIGs interact via physisorption. In contrast, the Rh-InS monolayer demonstrates strong chemisorption and distinct electronic responses to all five gases, driven by robust hybridization between the Rh-d and TIG-p orbitals. Based on comprehensive analyses of sensitivity and recovery time, Rh-InS is identified as a theoretically promising candidate for a reusable SO₂ sensor at room temperature, boasting a calculated rapid theoretical recovery time of 2.20 s. The Pt-InS system, conversely, shows potential for high-temperature NH₃ sensing. Our findings highlight the exceptional and tunable gas sensing capabilities of Pt- and Rh-decorated InS monolayers, offering a theoretical foundation for designing InS-based sensing devices. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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18 pages, 1830 KB

Open AccessArticle

Discovery of Novel Inhibitors of Aspergillus fumigatus DHODH via Virtual Screening, MD Simulation, and In Vitro Activity Assay

by Kaige Li, Wei Xia and John Z. H. Zhang

Molecules 2025, 30(12), 2607; https://doi.org/10.3390/molecules30122607 - 16 Jun 2025

Cited by 1 | Viewed by 1721

Abstract

To address the surge in Aspergillus fumigatus infections among immunosuppressed patients and azole resistance, this study focused on developing novel inhibitors targeting dihydroorotate dehydrogenase (AfDHODH), a key enzyme in fungal pyrimidine synthesis. The three-dimensional structure of AfDHODH was constructed via homology modeling. Molecular docking, dynamics simulations, and binding free energy calculations systematically elucidated the mechanisms of existing inhibitors. Virtual screening against the ZINC20 and ChEMBL databases yielded 13 candidates, with two micromolar inhibitors (IC₅₀ < 100 μM) identified through in vitro assays. These inhibitors exhibited novel scaffold structures that were distinct from known DHODH inhibitors. The results validate the feasibility of homology modeling-guided antifungal discovery and these findings provide critical insights for the development of new antifungal agents. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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24 pages, 3364 KB

Open AccessArticle

One-Pot Approach Towards Peptoids Synthesis Using 1,4-Dithiane-2,5-Diol via Multicomponent Approach and DFT-Based Computational Analysis

by Musrat Shaheen and Akbar Ali

Molecules 2025, 30(11), 2340; https://doi.org/10.3390/molecules30112340 - 27 May 2025

Cited by 1 | Viewed by 2580

Abstract

Peptoids are peptidomimetics in which the side chain is attached to the nitrogen of the amide group rather than the α-carbon. This alteration in the backbone structure is highly valued because it endows beneficial properties, including enhanced resistance to proteolysis, greater immunogenicity, improved biostability, and superior bioavailability. In this current study, we focused on the Ugi-4CR-based one-pot synthesis of peptoids using 1,4-dithiane-2,5-diol as the carbonyl component together with amine, carboxylic acid, and isocyanides. Four new peptoids—5a, 5b, 5c, and 5d—were designed and efficiently prepared in good chemical yields and were subjected to DFT investigations for their electronic behavior. These compounds have free OH, SH, and terminal triple bonds for further chemistry. In a computational analysis, the spectral data of compounds 5a–5d were juxtaposed with calculated spectral values derived from the B3LYP/6-311G(d,p) level. The electronic excitation and orbital contributions of 5a–5d were predicted using TD-DFT calculations. A natural bond order (NBO) analysis was utilized to investigate the electronic transition of newly synthesized peptoids, focusing on their charge distribution patterns. Furthermore, MEP and NPA analyses were conducted to predict charge distribution in these compounds. The reactivity and stability of the targeted peptoids were evaluated by global reactivity descriptors, which were determined with frontier molecular orbital analysis. The DFT results revealed that compound 5c displayed marginally higher reactivity compared to 5a, 5b, and 5d, possibly due to its extended conjugation. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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17 pages, 6900 KB

Open AccessArticle

Tuning the Energy Levels of Adamantane by Boron Substitution

by Aminu H. Yusuf, Vladimir B. Golovko and Sarah L. Masters

Molecules 2025, 30(9), 1976; https://doi.org/10.3390/molecules30091976 - 29 Apr 2025

Viewed by 1791

Abstract

Adamantane is known to have two different carbon environments, the C1-type (or bridgehead) and C2-type (or methylene bridge), serving as a foundation to explore the effects of boron substitution at these sites. Using DFT with B3LYP/6-31G(d), the structural, electronic, and optical properties of 37 boron-substituted isomers were investigated. The adamantane structure has rigid T_d symmetry with an average rC-C of 153.7 pm, which progressively transforms to C_3v and C₁ symmetry in heavily substituted isomers. Analysis of the neutral and ionic species reveals a critical transition from electron-donating to electron-accepting behaviour at tri-boron substitution, confirmed by both DFT and coupled cluster calculations (CCSD(T)/CC-pVDZ). C1 substitution narrows the HOMO–LUMO gap significantly, achieving a 56% reduction compared to 44.5% for C2 substitution in tetra-bora derivatives compared to adamantane. Optical properties [CAM-B3LYP/6-311G(d,p)] show systematic red shifting with increasing boron substitution, with absorption maxima moving from 146 nm in pristine adamantane to 423 nm (C1) and 277 nm (C2) in heavily boron-substituted derivatives (tetra-bora-adamantane). While C1 substitution leads to symmetry-forbidden transitions, C2 substitution maintains allowed transitions, offering more consistent optical behaviour. These findings provide important insight for the design of adamantane-based materials with tailored electronic and optical properties. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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11 pages, 1982 KB

Open AccessArticle

Hydroperoxyl Radical Scavenging Activity of Bromophenols from Marine Red Alga Polysiphonia urceolata: Mechanistic Insights, Kinetic Analysis, and Influence of Physiological Media

by Houssem Boulebd

Molecules 2025, 30(8), 1697; https://doi.org/10.3390/molecules30081697 - 10 Apr 2025

Cited by 1 | Viewed by 914

Abstract

Bromophenols (BPs), particularly those derived from marine sources, are known for their potent radical scavenging activity, effectively neutralizing reactive oxygen species (ROS). However, their exact mechanism of action remains largely unexplored, limiting our understanding of their potential as natural antioxidants. In this study, the antiradical mechanisms of two BP derivatives (1 and 2), previously isolated from the marine red alga Polysiphonia urceolata, were systematically investigated using thermodynamic and kinetic calculations. Both compounds demonstrated potent hydroperoxyl radical (HOO^•) scavenging activity in polar and lipid environments, with rate constants surpassing those of the well-known antioxidant standards Trolox and BHT. In lipid media, BP 2 exhibited approximately 600-fold greater activity than BP 1, with rate constants of 9.75 × 10⁵ and 1.64 × 10³ M⁻¹ s⁻¹, respectively. In contrast, both BPs showed comparable activity in aqueous media, with rate constants of 3.46 × 10⁸ and 9.67 × 10⁸ M⁻¹ s⁻¹ for 1 and 2, respectively. Mechanistic analysis revealed that formal hydrogen atom transfer (f-HAT) is the predominant pathway for radical scavenging in both lipid and polar environments. These findings provide critical insights into the antiradical mechanisms of natural BPs and underscore the potential of BP 1 and BP 2 as highly effective hydroperoxyl radical scavengers under physiological conditions. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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19 pages, 5194 KB

Open AccessArticle

Structural, Electronic, and Nonlinear Optical Characteristics of Europium-Doped Germanium Anion Nanocluster EuGe_n⁻ (n = 7–20): A Theoretical Investigation

by Chenliang Hao, Xueyan Dong, Chunli Li, Caixia Dong, Zhaofeng Yang and Jucai Yang

Molecules 2025, 30(6), 1377; https://doi.org/10.3390/molecules30061377 - 19 Mar 2025

Cited by 4 | Viewed by 1321

Abstract

Doping rare-earth metals into semiconductor germanium clusters can significantly enhance the stability of these clusters while introducing novel and noteworthy optical properties. Herein, a series of EuGe_n⁻ (n = 7–20) clusters and their structural and nonlinear optical properties are investigated via the ABCluster global search technique combined with the double-hybrid density functional theory mPW2PLYP. The structure growth pattern can be divided into two stages: an adsorption structure and a linked structure (when n = 7–10 and n = 11–20, respectively). In addition to simulating the photoelectron spectra of the clusters, their various properties, including their (hyper)polarizability, magnetism, charge transfer, relative stability, and energy gap, are identified. According to our examination, the EuGe₁₃⁻ cluster exhibits a significant nonlinear optical response of the β_tot value of 7.47 × 10⁵ a.u., and is thus considered a promising candidate for outstanding nonlinear optical semiconductor nanomaterials. Full article

(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Computational and Theoretical Chemistry)

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