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Pharmaceuticals
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Virtual Screening of Natural Product Databases for Drug Discovery
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Virtual Screening of Natural Product Databases for Drug Discovery

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (29 December 2023) | Viewed by 8079

Special Issue Editors

Dr. Paolo Governa

E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
Interests: molecular modeling; natural products; edible plants
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Fabrizio Manetti

E-Mail Website
Guest Editor
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy
Interests: drug design; molecular modeling; bioactive compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

For centuries, natural products have been the only source of bioactive compounds for therapeutic purposes. In the mid-1970s, they dominated the sources of novel human therapeutics in the pharmaceutical drug pipeline, particularly for cancer and infectious diseases. Indeed, two-thirds of the currently available drugs originated from unaltered natural products and their analogues, or contain natural product pharmacophores. Currently, approximately 200,000–250,000 natural products have been identified, but it is estimated that less than 10% of the world’s biodiversity has been evaluated for possible therapeutic applications. Despite being a proven source for modern small-molecule drug discovery, natural products also present challenges for drug discovery, such as technical barriers to isolation, characterization, screening, and optimization, which have contributed to a decline in their pursuit by the pharmaceutical industry. Natural products, indeed, are often structurally complex, presenting several hydroxyl and ketone substituents and many chiral centers, and usually have high polarity and molecular weight, which makes them unique and extremely diverse compared to synthetic molecules, but also very difficult to synthetize at a large scale. However, the advent of new technologies, such as improved analytical tools, genome mining and engineering strategies, microbial culturing advances, and computational methods, has allowed focus on the most promising candidates, thus opening new opportunities for natural products in drug discovery. In silico virtual screening is one of the most useful computational methods for filtering large databases of natural compounds. Several virtual screening protocols could be applied to natural product libraries, including, but not limited to, cheminformatics, ligand-, pharmacophore-, and structure-based approaches, machine learning, and molecular dynamics. This Special Issue will cover all different aspects of virtual screening methodology and applications, including ligand-, pharmacophore-, and structure-based approaches leading to the identification of hit compounds or to optimized leads. Potential topics include, but are not limited to:

  • Ligand-, pharmacophore-, and structure-based virtual screening of natural compounds;
  • Artificial intelligence applied to the discovery of drugs from natural sources;
  • Repurposing of natural drugs;
  • Hit-to-lead optimization of natural compounds;
  • Computational approaches for the prediction of the ADME properties of natural products.

Please note: experimental validation of in silico results is mandatory for this special issue.

Dr. Paolo Governa
Prof. Dr. Fabrizio Manetti
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. Pharmaceuticals 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 2900 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

  • virtual screening
  • natural products
  • pharmacophore modeling
  • molecular docking
  • drug discovery
  • hit-to-lead optimization
  • drug repurposing
  • ADME
  • artificial intelligence
  • machine learning

Published Papers (3 papers)

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Research

21 pages, 12137 KiB  
Article
Navigating the Chemical Space and Chemical Multiverse of a Unified Latin American Natural Product Database: LANaPDB
by Alejandro Gómez-García, Daniel A. Acuña Jiménez, William J. Zamora, Haruna L. Barazorda-Ccahuana, Miguel Á. Chávez-Fumagalli, Marilia Valli, Adriano D. Andricopulo, Vanderlan da S. Bolzani, Dionisio A. Olmedo, Pablo N. Solís, Marvin J. Núñez, Johny R. Rodríguez Pérez, Hoover A. Valencia Sánchez, Héctor F. Cortés Hernández and José L. Medina-Franco
Pharmaceuticals 2023, 16(10), 1388; https://doi.org/10.3390/ph16101388 - 30 Sep 2023
Cited by 1 | Viewed by 3021
Abstract
The number of databases of natural products (NPs) has increased substantially. Latin America is extraordinarily rich in biodiversity, enabling the identification of novel NPs, which has encouraged both the development of databases and the implementation of those that are being created or are [...] Read more.
The number of databases of natural products (NPs) has increased substantially. Latin America is extraordinarily rich in biodiversity, enabling the identification of novel NPs, which has encouraged both the development of databases and the implementation of those that are being created or are under development. In a collective effort from several Latin American countries, herein we introduce the first version of the Latin American Natural Products Database (LANaPDB), a public compound collection that gathers the chemical information of NPs contained in diverse databases from this geographical region. The current version of LANaPDB unifies the information from six countries and contains 12,959 chemical structures. The structural classification showed that the most abundant compounds are the terpenoids (63.2%), phenylpropanoids (18%) and alkaloids (11.8%). From the analysis of the distribution of properties of pharmaceutical interest, it was observed that many LANaPDB compounds satisfy some drug-like rules of thumb for physicochemical properties. The concept of the chemical multiverse was employed to generate multiple chemical spaces from two different fingerprints and two dimensionality reduction techniques. Comparing LANaPDB with FDA-approved drugs and the major open-access repository of NPs, COCONUT, it was concluded that the chemical space covered by LANaPDB completely overlaps with COCONUT and, in some regions, with FDA-approved drugs. LANaPDB will be updated, adding more compounds from each database, plus the addition of databases from other Latin American countries. Full article
(This article belongs to the Special Issue Virtual Screening of Natural Product Databases for Drug Discovery)
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19 pages, 4878 KiB  
Article
In Silico-Motivated Discovery of Novel Potent Glycogen Synthase-3 Inhibitors: 1-(Alkyl/arylamino)-3H-naphtho[1,2,3-de]quinoline-2,7-dione Identified as a Scaffold for Kinase Inhibitor Development
by Thomas D. Emmerich and Joseph M. Hayes
Pharmaceuticals 2023, 16(5), 661; https://doi.org/10.3390/ph16050661 - 28 Apr 2023
Cited by 1 | Viewed by 1583
Abstract
Glycogen synthase kinase-3 (GSK-3) isoforms α and β have diverse roles within cell biology, and have been linked with multiple diseases that include prominent CNS conditions such as Alzheimer’s disease and several psychiatric disorders. In this study, motivated by computation, we aimed to [...] Read more.
Glycogen synthase kinase-3 (GSK-3) isoforms α and β have diverse roles within cell biology, and have been linked with multiple diseases that include prominent CNS conditions such as Alzheimer’s disease and several psychiatric disorders. In this study, motivated by computation, we aimed to identify novel ATP-binding site inhibitors of GSK-3 with CNS-active potential. A ligand screening (docking) protocol against GSK-3β was first optimized, employing an active/decoy benchmarking set, with the final protocol selected based on statistical performance analysis. The optimized protocol involved pre-filtering of ligands using a three-point 3D-pharmacophore, followed by Glide-SP docking applying hinge region hydrogen bonding constraints. Using this approach, the Biogenic subset of the ZINC15 compound database was screened, focused on compounds with potential for CNS-activity. Twelve compounds (generation I) were selected for experimental validation using in vitro GSK-3β binding assays. Two hit compounds, 1 and 2, with 6-amino-7H-benzo[e]perimidin-7-one and 1-(phenylamino)-3H-naphtho[1,2,3-de]quinoline-2,7-dione type scaffolds were identified with IC50 values of 1.63 µM and 20.55 µM, respectively. Ten analogues of 2 (generation II) were selected for structure activity relationship (SAR) analysis and revealed four low micromolar inhibitors (<10 µM), with 19 (IC50 = 4.1 µM)~five times more potent than initial hit compound 2. Selectivity screening of low micromolar inhibitors 14 and 19 (comparing aryl- and alkyl-substituents) against 10 homologous kinases revealed unique selectivity profiles, with both compounds more potent against the GSK-3α isoform (IC50s~2 µM) and, additionally, inhibitors of PKBβ (IC50s < 25 µM). Compound 14 also inhibited ERK2 and 19, PKCγ, but generally good selectivity for GSK-3 isoforms over the other kinases was observed. The compounds had excellent predicted oral bioavailability and CNS-activity profiles, presenting promising candidates for future testing in cellular models of disease. Full article
(This article belongs to the Special Issue Virtual Screening of Natural Product Databases for Drug Discovery)
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20 pages, 3326 KiB  
Article
Autochthonous Peruvian Natural Plants as Potential SARS-CoV-2 Mpro Main Protease Inhibitors
by Maria Nuria Peralta-Moreno, Vanessa Anton-Muñoz, David Ortega-Alarcon, Ana Jimenez-Alesanco, Sonia Vega, Olga Abian, Adrian Velazquez-Campoy, Timothy M. Thomson, José Manuel Granadino-Roldán, Claudia Machicado and Jaime Rubio-Martinez
Pharmaceuticals 2023, 16(4), 585; https://doi.org/10.3390/ph16040585 - 13 Apr 2023
Cited by 3 | Viewed by 2233
Abstract
Over 750 million cases of COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), have been reported since the onset of the global outbreak. The need for effective treatments has spurred intensive research for therapeutic agents based on pharmaceutical repositioning or [...] Read more.
Over 750 million cases of COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), have been reported since the onset of the global outbreak. The need for effective treatments has spurred intensive research for therapeutic agents based on pharmaceutical repositioning or natural products. In light of prior studies asserting the bioactivity of natural compounds of the autochthonous Peruvian flora, the present study focuses on the identification SARS-CoV-2 Mpro main protease dimer inhibitors. To this end, a target-based virtual screening was performed over a representative set of Peruvian flora-derived natural compounds. The best poses obtained from the ensemble molecular docking process were selected. These structures were subjected to extensive molecular dynamics steps for the computation of binding free energies along the trajectory and evaluation of the stability of the complexes. The compounds exhibiting the best free energy behaviors were selected for in vitro testing, confirming the inhibitory activity of Hyperoside against Mpro, with a Ki value lower than 20 µM, presumably through allosteric modulation. Full article
(This article belongs to the Special Issue Virtual Screening of Natural Product Databases for Drug Discovery)
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