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Biomedicines
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Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties
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Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 10950

Special Issue Editors

Dr. Vikas Kumar

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Guest Editor
Basque Center for Materials, Applications, and Nanostructures (BCMaterials), Buil. Martina Casiano, Pl. 3 Parque Científico UPV/EHU Barrio Sarriena, 48940 Leioa, Spain
Interests: artificial intelligence and machine learning; QSAR; virtual screening; molecular dynamics simulations; hit identification
Special Issues, Collections and Topics in MDPI journals
Dr. Shraddha Parate

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Guest Editor
Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden
Interests: pharmacophore modeling; virtual screening; molecular docking; molecular dynamics simulations; machine learning

Special Issue Information

Dear Colleagues,

The journey of discovering effective treatments for infectious diseases and cancer has been a challenging and evolving process. Historically, drug discovery often relied on trial and error, resulting in lengthy and resource-intensive endeavors. However, the advent of computational methods has transformed this landscape, ushering in a new era of accelerated and targeted drug development. Infectious diseases, caused by pathogens such as bacteria, viruses, and parasites, have plagued humanity throughout history. Likewise, cancer, which is characterized by uncontrolled cell growth, has presented a substantial threat to public health. Over the years, researchers have pursued novel therapies through empirical testing and the screening of vast chemical libraries. However, these traditional methods often yielded limited success due to the complex nature of diseases and the immense diversity of potential drug candidates. In the realm of modern drug design, computer-aided molecular modeling and simulation techniques stand as indispensable tools. They empower researchers to identify potential drug candidates with greater efficiency and precision than conventional experimental approaches. With this Special Issue, our objective is to convene a collection of research articles from esteemed experts in the field. These contributions will spotlight a spectrum of both traditional and novel computational methods and strategies, all converging to unravel the process of drug design and development against therapeutic targets. Topics of interest for this Special Issue may include, but are not limited to, natural product-derived antimicrobials and anticancer compounds, in silico screening of small molecules, molecular dynamics simulations in rational drug design, machine learning approaches for drug design, network pharmacology for drug discovery, and the structure-based design of PROTACs.

Dr. Vikas Kumar
Dr. Shraddha Parate
Guest Editors

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 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

  • target identification and validation
  • high-throughput screening and hit identification
  • fragment-based drug design
  • drug repurposing
  • drug discovery
  • pharmacophore modeling and QSAR
  • structure-based drug design
  • molecular docking
  • molecular dynamics simulations
  • protein–protein interactions
  • innovative therapeutic modalities: PROTACs
  • machine learning and AI in virtual screening
  • network pharmacology

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Published Papers (5 papers)

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Research

14 pages, 3899 KiB  
Article
Development and Application of an In Vitro Drug Screening Assay for Schistosoma mansoni Schistosomula Using YOLOv5
by María Alejandra Villamizar-Monsalve, Javier Sánchez-Montejo, Julio López-Abán, Belén Vicente, Miguel Marín, Noelia Fernández-Ceballos, Rafael Peláez and Antonio Muro
Biomedicines 2024, 12(12), 2894; https://doi.org/10.3390/biomedicines12122894 - 19 Dec 2024
Viewed by 983
Abstract
Background: Schistosomiasis impacts over 230 million people globally, with 251.4 million needing treatment. The disease causes intestinal and urinary symptoms, such as hepatic fibrosis, hepatomegaly, splenomegaly, and bladder calcifications. While praziquantel (PZQ) is the primary treatment, its effectiveness against juvenile stages (schistosomula) is [...] Read more.
Background: Schistosomiasis impacts over 230 million people globally, with 251.4 million needing treatment. The disease causes intestinal and urinary symptoms, such as hepatic fibrosis, hepatomegaly, splenomegaly, and bladder calcifications. While praziquantel (PZQ) is the primary treatment, its effectiveness against juvenile stages (schistosomula) is limited, highlighting the need for new therapeutic agents, repurposed drugs, or reformulated compounds. Existing microscopy methods for assessing schistosomula viability are labor-intensive, subjective, and time-consuming. Methods: An artificial intelligence (AI)-assisted culture system using YOLOv5 was developed to evaluate compounds against Schistosoma mansoni schistosomula. The AI model, based on object detection, was trained on 4390 images distinguishing between healthy and damaged schistosomula. The system was externally validated against human counters, and a small-scale assay was performed to demonstrate its potential for larger-scale assays in the future. Results: The AI model exhibited high accuracy, achieving a mean average precision (mAP) of 0.966 (96.6%) and effectively differentiating between healthy and damaged schistosomula. External validation demonstrated significantly improved accuracy and counting time compared to human counters. A small-scale assay was conducted to validate the system, identifying 28 potential compounds with schistosomicidal activity against schistosomula in vitro and providing their preliminary LC50 values. Conclusions: This AI-powered method significantly improves accuracy and time efficiency compared to traditional microscopy. It enables the evaluation of compounds for potential schistosomiasis drugs without the need for dyes or specialized equipment, facilitating more efficient drug assessment. Full article
(This article belongs to the Special Issue Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties)
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18 pages, 3364 KiB  
Article
Superior Anticancer and Antifungal Activities of New Sulfanyl-Substituted Niclosamide Derivatives
by Jingyi Ma, Dileepkumar Veeragoni, Hindole Ghosh, Nicole Mutter, Gisele Barbosa, Lauren Webster, Rainer Schobert, Wendy van de Sande, Prasad Dandawate and Bernhard Biersack
Biomedicines 2024, 12(7), 1621; https://doi.org/10.3390/biomedicines12071621 - 21 Jul 2024
Cited by 2 | Viewed by 1744
Abstract
The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested [...] Read more.
The approved anthelmintic salicylanilide drug niclosamide has shown promising anticancer and antimicrobial activities. In this study, new niclosamide derivatives with trifluoromethyl, trifluoromethylsulfanyl, and pentafluorosulfanyl substituents replacing the nitro group of niclosamide were prepared (including the ethanolamine salts of two promising salicylanilides) and tested for their anticancer activities against esophageal adenocarcinoma (EAC) cells. In addition, antifungal activity against a panel of Madurella mycetomatis strains, the most abundant causative agent of the neglected tropical disease eumycetoma, was evaluated. The new compounds revealed higher activities against EAC and fungal cells than the parent compound niclosamide. The ethanolamine salt 3a was the most active compound against EAC cells (IC50 = 0.8–1.0 µM), and its anticancer effects were mediated by the downregulation of anti-apoptotic proteins (BCL2 and MCL1) and by decreasing levels of β-catenin and the phosphorylation of STAT3. The plausibility of binding to the latter factors was confirmed by molecular docking. The compounds 2a and 2b showed high in vitro antifungal activity against M. mycetomatis (IC50 = 0.2–0.3 µM) and were not toxic to Galleria mellonella larvae. Slight improvements in the survival rate of G. mellonella larvae infected with M. mycetomatis were observed. Thus, salicylanilides such as 2a and 3a can become new anticancer and antifungal drugs. Full article
(This article belongs to the Special Issue Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties)
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22 pages, 4817 KiB  
Article
An Exploration of the Inhibitory Mechanism of Rationally Screened Benzofuran-1,3,4-Oxadiazoles and-1,2,4-Triazoles as Inhibitors of NS5B RdRp Hepatitis C Virus through Pharmacoinformatic Approaches
by Ali Irfan, Shah Faisal, Sajjad Ahmad, Muhammad Jawwad Saif, Ameer Fawad Zahoor, Samreen Gul Khan, Jamila Javid, Sami A. Al-Hussain, Muhammed Tilahun Muhammed and Magdi E. A. Zaki
Biomedicines 2023, 11(11), 3085; https://doi.org/10.3390/biomedicines11113085 - 17 Nov 2023
Cited by 2 | Viewed by 1864
Abstract
Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1–BF7 and benzofuran-1,2,4-triazole compounds BF8–BF15 were tested against HCV [...] Read more.
Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1–BF7 and benzofuran-1,2,4-triazole compounds BF8–BF15 were tested against HCV NS5B RNA-dependent RNA polymerase (RdRp) utilizing structure-based screening via a computer-aided drug design (CADD) approach. A molecular docking approach was applied to evaluate the binding potential of benzofuran-appended 1,3,4-oxadiazole and 1,2,4-triazole BF1–BF15 molecules. Benzofuran-1,3,4-oxadiazole scaffolds BF1–BF7 showed lesser binding affinities (−12.63 to −14.04 Kcal/mol) than benzofuran-1,2,4-triazole scaffolds BF8–BF15 (−14.11 to −16.09 Kcal/mol) against the HCV NS5B enzyme. Molecular docking studies revealed the excellent binding affinity scores exhibited by benzofuran-1,2,4-triazole structural motifs BF-9 (−16.09 Kcal/mol), BF-12 (−15.75 Kcal/mol), and BF-13 (−15.82 Kcal/mol), respectively, which were comparatively better than benzofuran-based HCV NS5B inhibitors’ standard reference drug Nesbuvir (−15.42 Kcal/mol). A molecular dynamics simulation assay was also conducted to obtain valuable insights about the enzyme–compounds interaction profile and structural stability, which indicated the strong intermolecular energies of the BF-9+NS5B complex and the BF-12+NS5B complex as per the MM-PBSA method, while the BF-12+NS5B complex was the most stable system as per the MM-GBSA calculation. The drug-likeness and ADMET studies of all the benzofuran-1,2,4-triazole derivatives BF8–BF15 revealed that these compounds possessed good medicinal chemistry profiles in agreement with all the evaluated parameters for being drugs. The molecular docking affinity scores, MM-PBSA/MM-GBSA and MD-simulation stability analysis, drug-likeness profiling, and ADMET study assessment indicated that N-4-fluorophenyl-S-linked benzofuran-1,2,4-triazole BF-12 could be a future promising anti-HCV NS5B RdRp inhibitor therapeutic drug candidate that has a structural agreement with the Nesbuvir standard reference drug. Full article
(This article belongs to the Special Issue Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties)
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21 pages, 5469 KiB  
Article
Synthesis, Cytotoxic, and Computational Screening of Some Novel Indole–1,2,4-Triazole-Based S-Alkylated N-Aryl Acetamides
by Ameer Fawad Zahoor, Sadaf Saeed, Azhar Rasul, Razia Noreen, Ali Irfan, Sajjad Ahmad, Shah Faisal, Sami A. Al-Hussain, Muhammad Athar Saeed, Muhammed Tilahun Muhammed, Zeinab A. Muhammad and Magdi E. A. Zaki
Biomedicines 2023, 11(11), 3078; https://doi.org/10.3390/biomedicines11113078 - 16 Nov 2023
Cited by 6 | Viewed by 2388
Abstract
Molecular hybridization has emerged as the prime and most significant approach for the development of novel anticancer chemotherapeutic agents for combating cancer. In this pursuit, a novel series of indole–1,2,4-triazol-based N-phenyl acetamide structural motifs 8a–f were synthesized and screened against [...] Read more.
Molecular hybridization has emerged as the prime and most significant approach for the development of novel anticancer chemotherapeutic agents for combating cancer. In this pursuit, a novel series of indole–1,2,4-triazol-based N-phenyl acetamide structural motifs 8a–f were synthesized and screened against the in vitro hepatocellular cancer Hep-G2 cell line. The MTT assay was applied to determine the anti-proliferative potential of novel indole–triazole compounds 8a–f, which displayed cytotoxicity potential as cell viabilities at 100 µg/mL concentration, by using ellipticine and doxorubicin as standard reference drugs. The remarkable prominent bioactive structural hybrids 8a, 8c, and 8f demonstrated good-to-excellent anti-Hep-G2 cancer chemotherapeutic potential, with a cell viability of (11.72 ± 0.53), (18.92 ± 1.48), and (12.93 ± 0.55), respectively. The excellent cytotoxicity efficacy against the liver cancer cell line Hep-G2 was displayed by the 3,4-dichloro moiety containing indole–triazole scaffold 8b, which had the lowest cell viability (10.99 ± 0.59) compared with the standard drug ellipticine (cell viability = 11.5 ± 0.55) but displayed comparable potency in comparison with the standard drug doxorubicin (cell viability = 10.8 ± 0.41). The structure–activity relationship (SAR) of indole–triazoles 8a–f revealed that the 3,4-dichlorophenyl-based indole–triazole structural hybrid 8b displayed excellent anti-Hep-G2 cancer chemotherapeutic efficacy. The in silico approaches such as molecular docking scores, molecular dynamic simulation stability data, DFT, ADMET studies, and in vitro pharmacological profile clearly indicated that indole–triazole scaffold 8b could be the lead anti-Hep-G2 liver cancer therapeutic agent and a promising anti-Hep-G2 drug candidate for further clinical evaluations. Full article
(This article belongs to the Special Issue Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties)
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14 pages, 24376 KiB  
Article
The Antiviral Activity of Varenicline against Dengue Virus Replication during the Post-Entry Stage
by Ching-Lin Lin, Yan-Tung Kiu, Ju-Ying Kan, Yu-Jen Chang, Ping-Yi Hung, Chih-Hao Lu, Wen-Ling Lin, Yow-Wen Hsieh, Jung-Yie Kao, Nien-Jen Hu and Cheng-Wen Lin
Biomedicines 2023, 11(10), 2754; https://doi.org/10.3390/biomedicines11102754 - 11 Oct 2023
Cited by 4 | Viewed by 2058
Abstract
Dengue virus (DENV) poses a significant global health challenge, with millions of cases each year. Developing effective antiviral drugs against DENV remains a major hurdle. Varenicline is a medication used to aid smoking cessation, with anti-inflammatory and antioxidant effects. In this study, varenicline [...] Read more.
Dengue virus (DENV) poses a significant global health challenge, with millions of cases each year. Developing effective antiviral drugs against DENV remains a major hurdle. Varenicline is a medication used to aid smoking cessation, with anti-inflammatory and antioxidant effects. In this study, varenicline was investigated for its antiviral potential against DENV. This study provides evidence of the antiviral activity of varenicline against DENV, regardless of the virus serotype or cell type used. Varenicline demonstrated dose-dependent effects in reducing viral protein expression, infectivity, and virus yield in Vero and A549 cells infected with DENV-1 and DENV-2, with EC50 values ranging from 0.44 to 1.66 μM. Time-of-addition and removal experiments demonstrated that varenicline had a stronger inhibitory effect on the post-entry stage of DENV-2 replication than on the entry stage, as well as the preinfection and virus attachment stages. Furthermore, cell-based trans-cleavage assays indicated that varenicline dose-dependently inhibited the proteolytic activity of DENV-2 NS2B-NS3 protease. Docking models revealed the formation of hydrogen bonds and van der Waals forces between varenicline and specific residues in the DENV-1 and DENV-2 NS2B-NS3 proteases. These results highlight the antiviral activity and potential mechanism of varenicline against DENV, offering valuable insights for further research and development in the treatment of DENV infection. Full article
(This article belongs to the Special Issue Small Molecule Drug Discovery with Anti-microbial and Anti-cancer Properties)
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