Contribution of Computational Tools for Drug Development against Pathogens

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (20 January 2024) | Viewed by 6124

Special Issue Editors

Laboratório de Farmacologia e Bioquímica (LFBq), Departamento de Medicina Veterinária, Universidade de São Paulo Faculdade de Zootecnia e Engenharia de Alimentos, Pirassununga, SP 13635-900, Brazil
Interests: pathogen biochemistry and pharmacology; neglected disease (leishmaniasis); drug development
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: in silico pharmacology; computational toxicology; computer-aided drug design; modelling and simulation; infectious diseases
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Special Issue Information

Dear colleagues,

This Special Issue “Contribution of Computational Tools for Drug Development against Pathogens” welcomes submissions of review and research articles related to the contribution of computational tools for drug development against human and/or animal pathogens, as well as plant pathogens.

In silico studies can accelerate and guide drug discovery and therapeutic approaches. In this manner, we invite submissions of manuscripts that highlight and/or improve the use of tools such as docking analysis; in silico studies of pharmacokinetics parameters of absorption, distribution, metabolism, and excretion (ADME); and use of electronic tools to analyze data and/or Big Data related to animals and plants pathogens. Furthermore, studies on molecular modeling are also welcome.

In summary, this Special Issue plans to highlight the latest research on the use of in silico tools against pathogens. This Special Issues will be a guide for tools related to drug development and future collaborative research studies.

Dr. Edson Roberto da Silva
Dr. Simone Brogi
Guest Editor

Manuscript Submission Information

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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. Pathogens 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 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

  • in silico tools
  • pathogens
  • docking
  • ADME
  • drug design
  • drug screening
  • metabolic pathway
  • molecular modeling

Published Papers (3 papers)

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Research

22 pages, 2359 KiB  
Article
Selene-Ethylenelacticamides and N-Aryl-Propanamides as Broad-Spectrum Leishmanicidal Agents
by Natália Ferreira de Sousa, Helivaldo Diógenes da Silva Souza, Renata Priscila Barros de Menezes, Francinara da Silva Alves, Chonny Alexander Herrera Acevedo, Thaís Amanda de Lima Nunes, Zoe L. Sessions, Luciana Scotti, Eugene N. Muratov, Francisco Jaime Bezerra Mendonça-Junior, Klinger Antônio da Franca Rodrigues, Petrônio Filgueiras de Athayde Filho and Marcus Tullius Scotti
Pathogens 2023, 12(1), 136; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens12010136 - 13 Jan 2023
Cited by 1 | Viewed by 2340
Abstract
The World Health Organization classifies Leishmania as one of the 17 “neglected diseases” that burden tropical and sub-tropical climate regions with over half a million diagnosed cases each year. Despite this, currently available anti-leishmania drugs have high toxicity and the potential to be [...] Read more.
The World Health Organization classifies Leishmania as one of the 17 “neglected diseases” that burden tropical and sub-tropical climate regions with over half a million diagnosed cases each year. Despite this, currently available anti-leishmania drugs have high toxicity and the potential to be made obsolete by parasite drug resistance. We chose to analyze organoselenides for leishmanicidal potential given the reduced toxicity inherent to selenium and the displayed biological activity of organoselenides against Leishmania. Thus, the biological activities of 77 selenoesters and their N-aryl-propanamide derivatives were predicted using robust in silico models of Leishmania infantum, Leishmania amazonensis, Leishmania major, and Leishmania (Viannia) braziliensis. The models identified 28 compounds with >60% probability of demonstrating leishmanicidal activity against L. infantum, and likewise, 26 for L. amazonesis, 25 for L. braziliensis, and 23 for L. major. The in silico prediction of ADMET properties suggests high rates of oral absorption and good bioavailability for these compounds. In the in silico toxicity evaluation, only seven compounds showed signs of toxicity in up to one or two parameters. The methodology was corroborated with the ensuing experimental validation, which evaluated the inhibition of the Promastigote form of the Leishmania species under study. The activity of the molecules was determined by the IC50 value (µM); IC50 values < 20 µM indicated better inhibition profiles. Sixteen compounds were synthesized and tested for their activity. Eight molecules presented IC50 values < 20 µM for at least one of the Leishmania species under study, with compound NC34 presenting the strongest parasite inhibition profile. Furthermore, the methodology used was effective, as many of the compounds with the highest probability of activity were confirmed by the in vitro tests performed. Full article
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11 pages, 1581 KiB  
Article
Serendipitous Discovery of a Competitive Inhibitor of FraB, a Salmonella Deglycase and Drug Target
by Pankajavalli Thirugnanasambantham, Sravya Kovvali, Austin Cool, Yuan Gao, Anice Sabag-Daigle, Erin F. Boulanger, Mark Mitton-Fry, Angela Di Capua, Edward J. Behrman, Vicki H. Wysocki, Steffen Lindert, Brian M. M. Ahmer and Venkat Gopalan
Pathogens 2022, 11(10), 1102; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11101102 - 26 Sep 2022
Cited by 2 | Viewed by 1675
Abstract
Although salmonellosis, an infectious disease, is a significant global healthcare burden, there are no Salmonella-specific vaccines or therapeutics for humans. Motivated by our finding that FraB, a Salmonella deglycase responsible for fructose-asparagine catabolism, is a viable drug target, we initiated experimental and [...] Read more.
Although salmonellosis, an infectious disease, is a significant global healthcare burden, there are no Salmonella-specific vaccines or therapeutics for humans. Motivated by our finding that FraB, a Salmonella deglycase responsible for fructose-asparagine catabolism, is a viable drug target, we initiated experimental and computational efforts to identify inhibitors of FraB. To this end, our recent high-throughput screening initiative yielded almost exclusively uncompetitive inhibitors of FraB. In parallel with this advance, we report here how a separate structural and computational biology investigation of FrlB, a FraB paralog, led to the serendipitous discovery that 2-deoxy-6-phosphogluconate is a competitive inhibitor of FraB (KI ~ 3 μM). However, this compound was ineffective in inhibiting the growth of Salmonella in a liquid culture. In addition to poor uptake, cellular metabolic transformations by a Salmonella dehydrogenase and different phosphatases likely undermined the efficacy of 2-deoxy-6-phosphogluconate in live-cell assays. These insights inform our ongoing efforts to synthesize non-hydrolyzable/-metabolizable analogs of 2-deoxy-6-phosphogluconate. We showcase our findings largely to (re)emphasize the role of serendipity and the importance of multi-pronged approaches in drug discovery. Full article
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14 pages, 6630 KiB  
Article
In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in Escherichia coli as Leishmania amazonensis Arginase Inhibitors
by Julio Abel Alfredo dos Santos Simone Come, Yibin Zhuang, Tianzhen Li, Simone Brogi, Sandra Gemma, Tao Liu and Edson Roberto da Silva
Pathogens 2022, 11(9), 1020; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11091020 - 07 Sep 2022
Cited by 3 | Viewed by 1408
Abstract
Arginase is a metalloenzyme that plays a central role in Leishmania infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as Leishmania amazonensis arginase inhibitors. Here, we describe the inhibition of arginase in L. amazonensis by rosmarinic acid analogs ( [...] Read more.
Arginase is a metalloenzyme that plays a central role in Leishmania infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as Leishmania amazonensis arginase inhibitors. Here, we describe the inhibition of arginase in L. amazonensis by rosmarinic acid analogs (1–7) and new caffeic acid-derived amides (8–10). Caffeic acid esters and amides were produced by means of an engineered synthesis in E. coli and tested against L. amazonensis arginase. New amides (8–10) were biosynthesized in E. coli cultured with 2 mM of different combinations of feeding substrates. The most potent arginase inhibitors showed Ki(s) ranging from 2 to 5.7 μM. Compounds 2–4 and 7 inhibited L. amazonensis arginase (L-ARG) through a noncompetitive mechanism whilst compound 9 showed a competitive inhibition. By applying an in silico protocol, we determined the binding mode of compound 9. The competitive inhibitor of L-ARG targeted the key residues within the binding site of the enzyme, establishing a metal coordination bond with the metal ions and a series of hydrophobic and polar contacts supporting its micromolar inhibition of L-ARG. These results highlight that dihydroxycinnamic-derived compounds can be used as the basis for developing new drugs using a powerful tool based on the biosynthesis of arginase inhibitors. Full article
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