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Latest Advances in Protein-Ligand Interactions
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Latest Advances in Protein-Ligand Interactions

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

Deadline for manuscript submissions: closed (20 October 2025) | Viewed by 4326

Editor

Prof. Dr. Fabio Altieri

E-Mail Website
Guest Editor
Department of Biochemical Science “A. Rossi Fanelli”, Faculty of Pharmacy and Medicine, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Interests: oxidative stress; cellular biochemistry; signal transduction; protein–ligand interaction; bioactive compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is titled “Latest Advances in Protein-Ligand Interactions”. It will focus on recent studies aimed at investigating protein–ligand interactions with a special aim to elucidate molecular modes of action, the protein targets of drugs, natural compounds, and the cellular pathways involved. Protein–ligand interactions may affect both protein conformation and biological activity. However, knowledge of their molecular targets, their effects on protein structure, and how they can modulate different cellular pathways and functions is lacking for many bioactive compounds. Studies providing such information are welcomed and will help to elucidate the molecular bases for many drug activities and the development of new drugs. All papers will be fully open access upon publication after peer review.

Prof. Dr. Fabio Altieri
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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • protein–ligand interaction
  • molecular mode of actions
  • target identification
  • drug discovery
  • bioactive agents

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Published Papers (2 papers)

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Research

33 pages, 7434 KB  
Article
From Deep-Sea Natural Product to Optimized Therapeutics: Computational Design of Marizomib Analogs
by Nasser Alotaiq and Doni Dermawan
Int. J. Mol. Sci. 2025, 26(24), 12159; https://doi.org/10.3390/ijms262412159 - 18 Dec 2025
Cited by 1 | Viewed by 802
Abstract
The proteasome β5 subunit plays a central role in protein degradation and is an established therapeutic target in glioblastoma. Marizomib (MZB), a natural β5 inhibitor, has shown promising anticancer activity, yet suboptimal pharmacological properties limit its clinical translation. Using a comprehensive computational approach, [...] Read more.
The proteasome β5 subunit plays a central role in protein degradation and is an established therapeutic target in glioblastoma. Marizomib (MZB), a natural β5 inhibitor, has shown promising anticancer activity, yet suboptimal pharmacological properties limit its clinical translation. Using a comprehensive computational approach, this study aimed to identify and characterize novel MZB analogs with improved binding affinity, stability, and drug-like profiles. An integrative in silico study was performed, including molecular docking, frontier molecular orbital (FMO) analysis, pharmacophore modeling, molecular dynamics (MD) simulations over 200 ns, MM/PBSA binding free energy calculations, and per-residue energy decomposition. ADMET profiling evaluated the pharmacokinetic and safety properties of MZB and top-performing analogs. Docking and pharmacophore modeling revealed strong complementarity between MZB analogs and the β5 catalytic pocket. MD simulations showed that MZBMOD-77 and MZBMOD-79 exhibited exceptional structural stability with low RMSD values (0.40–0.42 nm), persistent binding within the active site cavity, and significant disruption of hydrogen-bond networks in the active loop regions Ala19–Lys33 and Val87–Gly98. MM/PBSA analysis confirmed their superior binding free energies (−19.99 and −18.79 kcal/mol, respectively), surpassing native MZB (−6.26 kcal/mol). Per-residue decomposition highlighted strong contributions from Arg19, Ala20, Lys33, and Ala50. ADMET predictions indicated improved oral absorption, reduced toxicity, and favorable pharmacokinetics compared to native MZB. This integrative computational study identifies MZBMOD-77 and MZBMOD-79 as promising next-generation proteasome β5 inhibitors. These analogs mimic and enhance the inhibitory mechanism of native MZB, offering potential candidates for further optimization and preclinical development in glioblastoma therapy. Full article
(This article belongs to the Special Issue Latest Advances in Protein-Ligand Interactions)
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22 pages, 2861 KB  
Article
Molecular Determinants for Guanine Binding in GTP-Binding Proteins: A Data Mining and Quantum Chemical Study
by Pawan Bhatta and Xiche Hu
Int. J. Mol. Sci. 2024, 25(22), 12449; https://doi.org/10.3390/ijms252212449 - 20 Nov 2024
Cited by 6 | Viewed by 2761
Abstract
GTP-binding proteins are essential molecular switches that regulate a wide range of cellular processes. Their function relies on the specific recognition and binding of guanine within their binding pockets. This study aims to elucidate the molecular determinants underlying this recognition. A large-scale data [...] Read more.
GTP-binding proteins are essential molecular switches that regulate a wide range of cellular processes. Their function relies on the specific recognition and binding of guanine within their binding pockets. This study aims to elucidate the molecular determinants underlying this recognition. A large-scale data mining of the Protein Data Bank yielded 298 GTP-binding protein complexes, which provided a structural foundation for a systematic analysis of the intermolecular interactions that are responsible for the molecular recognition of guanine in proteins. It was found that multiple modes of non-bonded interactions including hydrogen bonding, cation–π interactions, and π–π stacking interactions are employed by GTP-binding proteins for binding. Subsequently, the strengths of non-bonded interaction energies between guanine and its surrounding protein residues were quantified by means of the double-hybrid DFT method B2PLYP-D3/cc-pVDZ. Hydrogen bonds, particularly those involving the N2 and O6 atoms of guanine, confer specificity to guanine recognition. Cation–π interactions between the guanine ring and basic residues (Lys and Arg) provide significant electrostatic stabilization. π–π stacking interactions with aromatic residues (Phe, Tyr, and Trp) further contribute to the overall binding affinity. This synergistic interplay of multiple interaction modes enables GTP-binding proteins to achieve high specificity and stability in guanine recognition, ultimately underpinning their crucial roles in cellular signaling and regulation. Notably, the NKXD motif, while historically considered crucial for guanine binding in GTP-binding proteins, is not universally required. Our study revealed significant variability in hydrogen bonding patterns, with many proteins lacking the NKXD motif but still effectively binding guanine through alternative arrangements of interacting residues. Full article
(This article belongs to the Special Issue Latest Advances in Protein-Ligand Interactions)
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