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Molecular Docking in Drug Discovery, 2nd Edition
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Molecular Docking in Drug Discovery, 2nd Edition

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

Deadline for manuscript submissions: 30 September 2026 | Viewed by 7577

Special Issue Editor

Dr. Eleni Pontiki

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
Interests: medicinal chemistry; natural products; antioxidants; anti-inflammatory activity; pharmacokinetics; drug design; structure–activity relationships
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular docking remains a valuable tool in drug discovery. It is a fast and inexpensive technique for medicinal chemists to predict, identify, and synthesize compounds of potential biological interest, predict ligand-target interactions, or delineate structure–activity relationships (SAR) without the existence of other target modulators. Although initially, it was developed to identify the mechanisms and interactions of a ligand conformation within the binding pocket of a target molecule, many aspects remain challenging, and new approaches are being developed. 

This Special Issue describes traditional applications of molecular docking in drug discovery. Recent developments in molecular docking approaches include machine learning and applications such as drug repurposing, adverse effects, polypharmacology, etc. Examination of the various approaches and methods of molecular docking and an exploration of the techniques used for interpreting and validating docking results can be included.

This Special Issue covers the entire field of molecular docking in drug discovery and can contain reviews, research articles, and methodological papers. Manuscripts using structure-based drug design are welcome for targeted drug discovery rational synthesis of agents. Moreover, newer and emerging approaches and applications of molecular dockings, such as algorithms in fragment-based approaches, available benchmarking sets, consensus methods, and machine learning algorithms, can be submitted.

The scope also encompasses the integration of molecular docking with other computational techniques and all future applications when combined with emergent techniques, such as artificial intelligence.

Dr. Eleni Pontiki
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • computer aided drug design
  • drug discovery
  • molecular docking
  • structure–activity relationships
  • drug design

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Related Special Issue

Published Papers (5 papers)

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Research

23 pages, 4357 KB  
Article
α,β-Pipitzols and α,β-Isopipitzols from Natural Quinone Perezone: Quantum Chemistry, Docking, Chemoinformatic, and Pharmacological Studies
by Adriana Lizbeth Rivera Espejel, Joel Martínez, Cristopher Williams Fuentes Cid, Martha E. Macías Pérez, Maricarmen Hernández Rodríguez, Alejandro Fajardo De La Rosa, René Miranda Ruvalcaba and María Inés Nicolás-Vázquez
Molecules 2026, 31(3), 469; https://doi.org/10.3390/molecules31030469 - 29 Jan 2026
Viewed by 509
Abstract
PARP-1 and COX-2 have played important roles in several carcinomas, representing potential therapeutic targets; natural products have constituted interesting alternatives in cancer research, and complementary computational methods are relevant tools for the proposal of new molecules. Therefore, in this work, a theoretical study [...] Read more.
PARP-1 and COX-2 have played important roles in several carcinomas, representing potential therapeutic targets; natural products have constituted interesting alternatives in cancer research, and complementary computational methods are relevant tools for the proposal of new molecules. Therefore, in this work, a theoretical study of a set of four derivatives of perezone and isoperezone, i.e., α-pipitzol, β-pipitzol, α-isopipitzol, and β-isopipitzol, employing quantum chemistry, bioinformatics, and docking, was performed. Conformational studies were accomplished to obtain minimum energy structures. Subsequently, they were optimized by the B3LYP hybrid method and the 6-311++G(d,p) basis set. With this same level of theory, the geometrical, electronic, and spectroscopic properties and the reactivity parameters were determined; moreover, a molecular docking evaluation was performed to determine their activity towards COX-2 and PARP-1. Additionally, a cytotoxicity activity assay was performed against various cancer cell lines; thus, α-pipitzol and β-pipitzol showed the greatest affinity for COX-2, and the α-isopipitzol exhibited two relevant interactions. Regarding α-pipitzol, it exhibited both affinity and an important interaction with PARP-1. Regarding β-pipitzol, it displayed the lowest inhibitory concentration in A549 (64.49 µM); nevertheless, α-isopipitzol presented the lowest inhibitory concentrations, 83.59 µM and 87.85 µM for U37 and MCF-7 cell lines, respectively. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Discovery, 2nd Edition)
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23 pages, 11750 KB  
Article
Computational Identification of Blood–Brain Barrier-Permeant Microbiome Metabolites with Binding Affinity to Neurotransmitter Receptors in Neurodevelopmental Disorders
by Ricardo E. Buendia-Corona, María Fernanda Velasco Dey, Lisset Valencia Robles, Hannia Josselín Hernández-Biviano, Cristina Hermosillo-Abundis and Lucila Isabel Castro-Pastrana
Molecules 2026, 31(2), 366; https://doi.org/10.3390/molecules31020366 - 20 Jan 2026
Viewed by 943
Abstract
The gut microbiome produces thousands of metabolites with potential to modulate central nervous system function through peripheral or direct neural mechanisms. Tourette syndrome, attention-deficit/hyperactivity disorder, and autism spectrum disorder exhibit shared neurotransmitter dysregulation and microbiome alterations, yet mechanistic links between microbial metabolites and [...] Read more.
The gut microbiome produces thousands of metabolites with potential to modulate central nervous system function through peripheral or direct neural mechanisms. Tourette syndrome, attention-deficit/hyperactivity disorder, and autism spectrum disorder exhibit shared neurotransmitter dysregulation and microbiome alterations, yet mechanistic links between microbial metabolites and receptor-mediated neuromodulation remain unclear. We screened 27,642 microbiome SMILES metabolites for blood–brain barrier permeability using rule-based SwissADME classification and a PyTorch 2.0 neural network trained on 7807 experimental compounds (test accuracy 86.2%, AUC 0.912). SwissADME identified 1696 BBB-crossing metabolites following Lipinski’s criteria, while PyTorch classified 2484 metabolites with expanded physicochemical diversity. Following 3D conformational optimization (from SMILES) and curation based on ≤32 rotatable bonds, molecular docking was performed against five neurotransmitter receptors representing ionotropic (GABRA2, GRIA2, GRIN2B) and metabotropic (DRD4, HTR1A) receptor classes. The top 50 ligands across five receptors demonstrated method-specific BBB classification (44% SwissADME-only, 44% PyTorch-only, 12% overlap), validating complementary prediction approaches. Fungal metabolites from Ascomycota dominated high-affinity top ligands (66%) and menaquinone MK-7 showed broad phylogenetic conservation (71.4% of phylum). Our results establish detailed receptor–metabolite interaction maps, with fungal metabolites dominating high-affinity ligands, challenging the prevailing bacterial focus of the microbiome and providing a foundation for precision medicine and a framework for developing microbiome-targeted therapeutics to address clinical needs in neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Discovery, 2nd Edition)
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25 pages, 14971 KB  
Article
Targeting Anti-Apoptotic Bcl-2 Proteins with Triterpene-Heterocyclic Derivatives: A Combined Dual Docking and Molecular Dynamics Study
by Marius Mioc, Silvia Gruin, Armand Gogulescu, Oana Bătrîna, Mihaela Jorgovan, Bogdan-Ionuț Mara and Codruța Șoica
Molecules 2025, 30(19), 3919; https://doi.org/10.3390/molecules30193919 - 29 Sep 2025
Cited by 2 | Viewed by 1157
Abstract
Anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-xL, and Mcl-1), are often overexpressed in cancer, which aids tumor growth and treatment resistance. As a result, these proteins are excellent candidates for novel anticancer drugs. Within this study a virtual library of betuline derivatives was built [...] Read more.
Anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-xL, and Mcl-1), are often overexpressed in cancer, which aids tumor growth and treatment resistance. As a result, these proteins are excellent candidates for novel anticancer drugs. Within this study a virtual library of betuline derivatives was built and screened for possible Bcl-2, Bcl-XL, and Mcl-1 inhibitors. For every target, molecular docking simulations were performed using two different engines (AutoDock Vina and Glide). The ligands that most frequently appeared among the top candidates were shortlisted after comparing the top-20 hits from both docking scoring functions. To assess binding stability, five of these promising compounds were chosen and run through 100 ns molecular dynamics (MD) simulations in complex with every target protein. Key persistent intermolecular contacts were identified from MD contact frequency histograms, and stability was evaluated using root-mean-square deviation (RMSD) profiles of protein–ligand complexes following equilibration. Additionally, Prime MM-GBSA binding energies (ΔG_bind) for the 15 docked complexes were computed, and ligand efficiency was reported. Two substances, BOxNaf1 and BT3, stood out among the screened derivatives as the most stable binders to all three Bcl-2 family targets according to the dual docking and MD analysis approach. When the MM-GBSA and RMSF/rGyr data are considered alongside docking and MD stability, BOxNaf1 and BOxPhCl1 emerge as the most compelling dual/multi-target candidates, whereas BT3, though MD stable, shows weaker MM-GBSA energetics and is retained as a lower-priority backup chemotype. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Discovery, 2nd Edition)
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19 pages, 2360 KB  
Article
Novel N-Alkyl 3-(3-Benzyloxyquinoxalin-2-yl) Propanamides as Antiproliferative Agents: Design, Synthesis, In Vitro Testing, and In Silico Mechanistic Study
by Samar A. Abubshait
Molecules 2025, 30(14), 3025; https://doi.org/10.3390/molecules30143025 - 18 Jul 2025
Viewed by 1887
Abstract
A series of eleven new N-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and hydrophile characters to a quinoxaline [...] Read more.
A series of eleven new N-alkyl 3-(3-benzyloxyquinoxalin-2-yl) propanamides were prepared based on the azide coupling of 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide with a variety of primary and secondary amines and the consequent conjunction of a broad spectrum of lipophile and hydrophile characters to a quinoxaline ring system. 3-(3-benzyloxyquinoxalin-2-yl) propanhydrazide was produced in a two-step reaction of methyl 3-(3-oxo-3,4-dihydroquinoxalin-2-yl) propanoate with benzyl chloride followed by the hydrazinolysis of the corresponding ester. The antiproliferative activity of the compounds was tested in various cancer cell lines, including PC-3, Hela, HCT-116, and MCF-7; they showed a wide spectrum of activity for most of the tested compounds. Compound 6k exhibited the highest activity, which was comparable to that of doxorubicin, with IC50 (µM) values of 12.17 ± 0.9, 9.46 ± 0.7, 10.88 ± 0.8, and 6.93 ± 0.4 µM compared to 8.87 ± 0.6, 5.57 ± 0.4, 5.23 ± 0.3, and 4.17 ± 0.2 µM for doxorubicin against Hela, HCT-116, and MCF-7, respectively. The in silico mechanistic study revealed the inhibition of HDAC-6 through the binding of the unique zinc finger ubiquitin-binding domain (HDAC6 Zf-UBD). The docking results showed a specific binding pattern that emphasized the crucial role of the quinoxaline ring and its substituents. The newly developed derivatives were evaluated for antitumor effects against four cancer cell lines PC-3, HeLa, HCT-116, and MCF-7. This research led to the identification of a quinoxaline-based scaffold exhibiting broad-spectrum antiproliferative activity and a distinct mechanism involving binding to HDAC6 Zf-UBD. The findings highlight its potential for further optimization and preclinical studies to support future anticancer drug development. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Discovery, 2nd Edition)
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18 pages, 1571 KB  
Article
One-Pot Synthesis of Novel Pyrimidine Derivatives with Potential Antidiabetic Activity Through Dual α-Glucosidase and α-Amylase Inhibitors
by Ohood Al-Shehri, Samar Abubshait, Muhammad Nawaz, Mohamed S. Gomaa and Haya A. Abubshait
Molecules 2025, 30(13), 2857; https://doi.org/10.3390/molecules30132857 - 4 Jul 2025
Cited by 4 | Viewed by 1916
Abstract
This study describes the synthesis of heterocyclic derivatives containing multiple nitrogen atoms serving as important moieties for developing novel antidiabetics through a simple synthetic pathway. We herein describe the synthesis and characterization of novel pyrimidine derivatives using one-pot reactions in a catalyst-free and [...] Read more.
This study describes the synthesis of heterocyclic derivatives containing multiple nitrogen atoms serving as important moieties for developing novel antidiabetics through a simple synthetic pathway. We herein describe the synthesis and characterization of novel pyrimidine derivatives using one-pot reactions in a catalyst-free and efficient manner through a two-stage process involving the synthesis of 2-amino-4-hydrazinyl-6-methoxy pyrimidine, followed by a reaction with phenyl isothiocyanate derivatives. The structures of all the new compounds were confirmed via physical and spectral analysis. Furthermore, we evaluated the synthesized pyrimidine derivatives’ biological activities in relation to their potential roles as novel anti-diabetic agents by testing their activity profiles against the enzymes α-glucosidase and α-amylase. Compound 4 expressed the highest level of activity against α-glucosidase and α-amylase, with a greater inhibitory concentration (IC50 of 12.16 ± 0.12 µM and IC50 11.13 ± 0.12 µM) compared to that of acarbose (IC50 = 10.60 ± 0.17 µM and IC50 = 11.30 ± 0.12 µM), which is widely used as a standard antidiabetic drug. The primary structure activity relationship analysis identified the impact of an electron- withdrawing group, especially with respect to fluorine on inhibitory activity. This was further confirmed in molecular docking studies, which demonstrated that both compounds exhibited similar inhibition patterns and emphasized the significance of incorporating a lipophilic electron-withdrawing substituent on the phenyl ring, along with the 2,4-diaminopyrimidine scaffold. Full article
(This article belongs to the Special Issue Molecular Docking in Drug Discovery, 2nd Edition)
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