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Computational Approaches in Antimicrobial and Antiviral Drug Discovery: Deciphering Drug Binding and Molecular Mechanisms

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

Deadline for manuscript submissions: closed (30 April 2025) | Viewed by 3355

Special Issue Editors


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Guest Editor
Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: structural bioinformatics; molecular modeling; molecular dynamics; molecular docking; macromolecule electrostatics
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: molecular dynamics; virtual screening; molecular modelling; bioinformatics; computational chemistry

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Guest Editor
Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
Interests: antiviral drugs; respiratory viruses; virus morphogenesis; viral glycoproteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Nowadays, there is an increasing demand for antimicrobial and antiviral molecules counteracting the rising threats posed by emerging pathogens, as underlined by recent epidemics outbreaks such as the SARS-CoV-2 pandemic.

Currently, vaccines against many human viral diseases are not yet available; even where the vaccine is effective, the percentage of people who have received the vaccination worldwide may be lower than needed to achieve herd immunity and prevent transmission of viral diseases. For this reason, drug therapy is often still the gold standard for counteracting viral infections.

To address this challenge, it is essential to focus research efforts on novel therapeutic approaches, promoting collaboration among scientists from different fields and backgrounds.

Central to drug design and development strategies is the challenge of deciphering the molecular details of drug activity, particularly the specific interactions occurring between potential drugs and their targets. In this context, significant improvements have been made by the continuous development of computational techniques, which not only accelerate the selection or de novo design of potential lead compounds, but also provide a comprehensive and detailed understanding of the biological process under study. The use of in silico techniques for the preliminary stages of drug discovery, followed by experimental validation of promising candidates, can significantly expedite the identification of effective antimicrobial or antiviral agents and therapeutic strategies.

This Special Issue aims to gather latest research focusing on the discovery of novel antimicrobial or antiviral agents, and the identification of the molecular mechanisms underlying their effects, highlighting the pivotal role of in silico studies during the early phases of the drug discovery process. Research topics covered by this Special Issue include the application of various computational methods, such as (but not limited to) molecular modelling, molecular docking, molecular dynamics simulations, enhanced sampling methods, drug discovery approaches based on artificial intelligence or related computational techniques.

Original research and review articles addressing the evaluation of promising antimicrobial or antiviral compounds are welcomed, with a focus on the molecular basis of their mechanism of action against microrganisms. While papers presenting an integrated computational and experimental approach are encouraged, thorough computational studies will also be considered.

Dr. Mattia Falconi
Dr. Alice Romeo
Dr. Simone La Frazia
Guest Editors

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Keywords

  • molecular docking
  • virtual screening
  • molecular dynamics simulations
  • artificial intelligence
  • antimicrobial or antiviral activity
  • computational drug discovery
  • molecular mechanisms
  • experimental assays

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Published Papers (3 papers)

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Research

13 pages, 2806 KiB  
Article
Computational Design and Evaluation of Peptides to Target SARS-CoV-2 Spike–ACE2 Interaction
by Saja Almabhouh, Erika Cecon, Florence Basubas, Ruben Molina-Fernandez, Tomasz Maciej Stepniewski, Jana Selent, Ralf Jockers, Amal Rahmeh, Baldo Oliva and Narcis Fernandez-Fuentes
Molecules 2025, 30(8), 1750; https://doi.org/10.3390/molecules30081750 - 14 Apr 2025
Viewed by 316
Abstract
The receptor-binding domain (RBD) of SARS-CoV-2 spike protein is responsible for the recognition of the Angiotensin-Converting Enzyme 2 (ACE2) receptor in human cells and, thus, plays a critical role in viral infection. The therapeutic value of targeting this interaction has been proven by [...] Read more.
The receptor-binding domain (RBD) of SARS-CoV-2 spike protein is responsible for the recognition of the Angiotensin-Converting Enzyme 2 (ACE2) receptor in human cells and, thus, plays a critical role in viral infection. The therapeutic value of targeting this interaction has been proven by a sizable body of research investigating antibodies, small proteins, aptamers, and peptides. This study presents a novel peptide that impinges the interaction between RBD and ACE2. Starting from a very large pool of structurally designed peptides extracted from our database, PepI-Covid19, a diverse set of peptides were studied using molecular dynamics simulations. Ten of the most promising were chemically synthesized and validated both in vitro and in a cell-based assay. Our results indicate that one of the peptides (PEP10) exhibited the highest disruption of the RBD/ACE2 complex, effectively blocking the binding of two molecules and consequently inhibiting the SARS-CoV-2 spike-mediated cell entry of viruses pseudotyped with the spike of the D614G, Delta, and Omicron variants. PEP10 can potentially serve as a scaffold that can be further optimized for improved affinity and efficacy. Full article
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20 pages, 12099 KiB  
Article
Antimicrobial Peptide Databases as the Guiding Resource in New Antimicrobial Agent Identification via Computational Methods
by Bogdan Marczak, Aleksandra Bocian and Andrzej Łyskowski
Molecules 2025, 30(6), 1318; https://doi.org/10.3390/molecules30061318 - 14 Mar 2025
Viewed by 523
Abstract
In light of the growing interest in antimicrobial peptides (AMPs) as potential alternatives to traditional antibiotics, proteomic research has increasingly focused on this area. Addressing this significant scientific need, we undertook an initiative to review and analyze the available databases containing information on [...] Read more.
In light of the growing interest in antimicrobial peptides (AMPs) as potential alternatives to traditional antibiotics, proteomic research has increasingly focused on this area. Addressing this significant scientific need, we undertook an initiative to review and analyze the available databases containing information on AMPs. These databases play a pivotal role as a foundation for most AMP-related studies, enabling not only the identification of new compounds, but also a deeper understanding of their properties and therapeutic potential. As part of this study, we evaluated the quality of information within selected AMP databases, considering their accessibility, content, and research potential. The initial step of the analysis involved a comparison of the per-database and cross-database peptide sequences. A diamond, high-throughput protein alignment program was used to compare the degree of sequence similarity among peptides across the individual databases. The redundancy of the data was also evaluated. Collected information was used for an in silico evaluation of the selected species’ venom proteomes in order to identify putative antimicrobial peptide candidates. An example candidate was further evaluated via a combination of structural analysis based on the computed homology based structural model, the in silico digestion of the source protein, and the antimicrobial potential. Full article
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28 pages, 5649 KiB  
Article
Unlocking Antimicrobial Peptides: In Silico Proteolysis and Artificial Intelligence-Driven Discovery from Cnidarian Omics
by Ricardo Alexandre Barroso, Guillermin Agüero-Chapin, Rita Sousa, Yovani Marrero-Ponce and Agostinho Antunes
Molecules 2025, 30(3), 550; https://doi.org/10.3390/molecules30030550 - 25 Jan 2025
Cited by 1 | Viewed by 1681
Abstract
Overcoming the growing challenge of antimicrobial resistance (AMR), which affects millions of people worldwide, has driven attention for the exploration of marine-derived antimicrobial peptides (AMPs) for innovative solutions. Cnidarians, such as corals, sea anemones, and jellyfish, are a promising valuable resource of these [...] Read more.
Overcoming the growing challenge of antimicrobial resistance (AMR), which affects millions of people worldwide, has driven attention for the exploration of marine-derived antimicrobial peptides (AMPs) for innovative solutions. Cnidarians, such as corals, sea anemones, and jellyfish, are a promising valuable resource of these bioactive peptides due to their robust innate immune systems yet are still poorly explored. Hence, we employed an in silico proteolysis strategy to search for novel AMPs from omics data of 111 Cnidaria species. Millions of peptides were retrieved and screened using shallow- and deep-learning models, prioritizing AMPs with a reduced toxicity and with a structural distinctiveness from characterized AMPs. After complex network analysis, a final dataset of 3130 Cnidaria singular non-haemolytic and non-toxic AMPs were identified. Such unique AMPs were mined for their putative antibacterial activity, revealing 20 favourable candidates for in vitro testing against important ESKAPEE pathogens, offering potential new avenues for antibiotic development. Full article
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