Editorial

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2 pages, 182 KiB

Open AccessEditorial

Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products

by José L. Medina-Franco

Biomolecules 2021, 11(5), 630; https://doi.org/10.3390/biom11050630 - 23 Apr 2021

Cited by 3 | Viewed by 2008

Abstract

Natural products continue to be a significant source of active compounds [...] Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

Research

Jump to: Editorial, Review

25 pages, 5028 KiB

Open AccessArticle

Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

by Seth O. Asiedu, Samuel K. Kwofie, Emmanuel Broni and Michael D. Wilson

Biomolecules 2021, 11(5), 653; https://doi.org/10.3390/biom11050653 - 29 Apr 2021

Cited by 24 | Viewed by 4870

Abstract

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. [...] Read more.

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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19 pages, 15361 KiB

Open AccessArticle

Chemoinformatics Studies on a Series of Imidazoles as Cruzain Inhibitors

by Alex R. Medeiros, Leonardo L. G. Ferreira, Mariana L. de Souza, Celso de Oliveira Rezende Junior, Rocío Marisol Espinoza-Chávez, Luiz Carlos Dias and Adriano D. Andricopulo

Biomolecules 2021, 11(4), 579; https://doi.org/10.3390/biom11040579 - 15 Apr 2021

Cited by 10 | Viewed by 2808

Abstract

Natural products based on imidazole scaffolds have inspired the discovery of a wide variety of bioactive compounds. Herein, a series of imidazoles that act as competitive and potent cruzain inhibitors was investigated using a combination of ligand- and structure-based drug design strategies. Quantitative [...] Read more.

Natural products based on imidazole scaffolds have inspired the discovery of a wide variety of bioactive compounds. Herein, a series of imidazoles that act as competitive and potent cruzain inhibitors was investigated using a combination of ligand- and structure-based drug design strategies. Quantitative structure–activity relationships (QSARs) were generated along with the investigation of enzyme–inhibitor molecular interactions. Predictive hologram QSAR (HQSAR, r²_pred = 0.80) and AutoQSAR (q² = 0.90) models were built, and key structural properties that underpin cruzain inhibition were identified. Moreover, comparative molecular field analysis (CoMFA, r²_pred = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r²_pred = 0.73) revealed 3D molecular features that strongly affect the activity of the inhibitors. These findings were examined along with molecular docking studies and were highly compatible with the intermolecular contacts that take place between cruzain and the inhibitors. The results gathered herein revealed the main factors that determine the activity of the imidazoles studied and provide novel knowledge for the design of improved cruzain inhibitors. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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19 pages, 6125 KiB

Open AccessArticle

Structure and Location of Protein Sites Binding Self-Associated Congo Red Molecules with Intercalated Drugs as Compact Ligands—Theoretical Studies

by Ptak-Kaczor Magdalena, Kwiecińska Klaudia, Korchowiec Jacek, Chłopaś Katarzyna, Banach Mateusz, Roterman Irena and Jagusiak Anna

Biomolecules 2021, 11(4), 501; https://doi.org/10.3390/biom11040501 - 26 Mar 2021

Cited by 3 | Viewed by 1865

Abstract

In the search for new carriers capable of transporting toxic drugs to a target, particular attention has been devoted to supramolecular systems with a ribbon-like micellar structure of which Congo red is an example. A special promise of the possible use of such [...] Read more.

In the search for new carriers capable of transporting toxic drugs to a target, particular attention has been devoted to supramolecular systems with a ribbon-like micellar structure of which Congo red is an example. A special promise of the possible use of such systems for directing drugs to a target emerges from their particular affinity to immune complexes and as an independent property, binding many organic compounds including drugs by intercalation. Serum albumin also appeared able to bind micellar particles of such systems. It may protect them against dilution in transport. The mathematical tool, which relies on analysis of the distribution of polarity and hydrophobicity in protein molecules (fuzzy oil drop model), has been used to find the location of binding area in albumin as well as anchorage site for Congo red in heated IgG light chain used as a model presenting immunoglobulin-like structures. Results confirm the suggested formerly binding site of Congo red in V domain of IgG light chain and indicated the cleft between pseudo-symmetric domains of albumin as the area of attachment for the dye. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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25 pages, 5809 KiB

Open AccessArticle

Description and Analysis of Glycosidic Residues in the Largest Open Natural Products Database

by Jonas Schaub, Achim Zielesny, Christoph Steinbeck and Maria Sorokina

Biomolecules 2021, 11(4), 486; https://doi.org/10.3390/biom11040486 - 24 Mar 2021

Cited by 5 | Viewed by 2659

Abstract

Natural products (NPs), biomolecules produced by living organisms, inspire the pharmaceutical industry and research due to their structural characteristics and the substituents from which they derive their activities. Glycosidic residues are frequently present in NP structures and have particular pharmacokinetic and pharmacodynamic importance [...] Read more.

Natural products (NPs), biomolecules produced by living organisms, inspire the pharmaceutical industry and research due to their structural characteristics and the substituents from which they derive their activities. Glycosidic residues are frequently present in NP structures and have particular pharmacokinetic and pharmacodynamic importance as they improve their solubility and are often involved in molecular transport, target specificity, ligand–target interactions, and receptor binding. The COlleCtion of Open Natural prodUcTs (COCONUT) is currently the largest open database of NPs, and therefore a suitable starting point for the detection and analysis of the diversity of glycosidic residues in NPs. In this work, we report and describe the presence of circular, linear, terminal, and non-terminal glycosidic units in NPs, together with their importance in drug discovery. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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17 pages, 3699 KiB

Open AccessArticle

Chemoinformatic Screening for the Selection of Potential Senolytic Compounds from Natural Products

by Oscar Salvador Barrera-Vázquez, Juan Carlos Gómez-Verjan and Gil Alfonso Magos-Guerrero

Biomolecules 2021, 11(3), 467; https://doi.org/10.3390/biom11030467 - 22 Mar 2021

Cited by 13 | Viewed by 4183

Abstract

Cellular senescence is a cellular condition that involves significant changes in gene expression and the arrest of cell proliferation. Recently, it has been suggested in experimental models that the elimination of senescent cells with pharmacological methods delays, prevents, and improves multiple adverse outcomes [...] Read more.

Cellular senescence is a cellular condition that involves significant changes in gene expression and the arrest of cell proliferation. Recently, it has been suggested in experimental models that the elimination of senescent cells with pharmacological methods delays, prevents, and improves multiple adverse outcomes related to age. In this sense, the so-called senoylitic compounds are a class of drugs that selectively eliminates senescent cells (SCs) and that could be used in order to delay such adverse outcomes. Interestingly, the first senolytic drug (navitoclax) was discovered by using chemoinformatic and network analyses. Thus, in the present study, we searched for novel senolytic compounds through the use of chemoinformatic tools (fingerprinting and network pharmacology) over different chemical databases (InflamNat and BIOFACQUIM) coming from natural products (NPs) that have proven to be quite remarkable for drug development. As a result of screening, we obtained three molecules (hinokitiol, preussomerin C, and tanshinone I) that could be considered senolytic compound candidates since they share similarities in structure with senolytic leads (tunicamycin, ginsenoside Rb1, ABT 737, rapamycin, navitoclax, timosaponin A-III, digoxin, roxithromycin, and azithromycin) and targets involved in senescence pathways with potential use in the treatment of age-related diseases. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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13 pages, 2813 KiB

Open AccessArticle

Dilignans with a Chromanol Motif Discovered by Molecular Networking from the Stem Barks of Magnolia obovata and Their Proprotein Convertase Subtilisin/Kexin Type 9 Expression Inhibitory Activity

by Jongmin Ahn, Hee-Sung Chae, Pisey Pel, Young-Mi Kim, Young Hee Choi, Jinwoong Kim and Young-Won Chin

Biomolecules 2021, 11(3), 463; https://doi.org/10.3390/biom11030463 - 19 Mar 2021

Cited by 3 | Viewed by 2419

Abstract

Natural products have been fundamental materials in drug discovery. Traditional strategies for observing natural products with novel structure and/or biological activity are challenging due to large cost and time consumption. Implementation of the MS/MS-based molecular networking strategy with the in silico annotation tool [...] Read more.

Natural products have been fundamental materials in drug discovery. Traditional strategies for observing natural products with novel structure and/or biological activity are challenging due to large cost and time consumption. Implementation of the MS/MS-based molecular networking strategy with the in silico annotation tool is expected to expedite the dereplication of secondary metabolites. In this study, using this tool, two new dilignans with a 2-phenyl-3-chromanol motif, obovatolins A (1) and B (2), were discovered from the stem barks of Magnolia obovata Thunb. along with six known compounds (3–8), expanding chemical diversity of lignan skeletons in this natural source. Their structures and configurations were elucidated using spectroscopic data. All isolates were evaluated for their PCSK9 mRNA expression inhibitory activity. Obovatolins A (1) and B (2), and magnolol (3) showed potent lipid controlling activities. To identify transcriptionally controlled genes by 1 along with downregulation of PCSK9, using small set of genes (42 genes) related to lipid metabolism selected from the database, focused bioinformatic analysis was carried out. As a result, it showed the correlations between gene expression under presence of 1, which led to detailed insight of the lipid metabolism caused by 1. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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26 pages, 13075 KiB

Open AccessArticle

Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19)

by Amr El-Demerdash, Ahmed M. Metwaly, Afnan Hassan, Tarek Mohamed Abd El-Aziz, Eslam B. Elkaeed, Ibrahim H. Eissa, Reem K. Arafa and James D. Stockand

Biomolecules 2021, 11(3), 460; https://doi.org/10.3390/biom11030460 - 19 Mar 2021

Cited by 67 | Viewed by 5744

Abstract

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine [...] Read more.

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (M^pro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = −8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = −6.49 kcal/mol), and nsp10 (ΔG = −9.06 kcal/mol). Compound 13 showed promising binding affinities against M^pro (ΔG = −7.99 kcal/mol), spike glycoproteins (ΔG = −6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = −8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD₅₀, rat maximum tolerated dose, rat oral LD₅₀, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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12 pages, 9708 KiB

Open AccessArticle

QSAR-Based Virtual Screening of Natural Products Database for Identification of Potent Antimalarial Hits

by Letícia Tiburcio Ferreira, Joyce V. B. Borba, José Teófilo Moreira-Filho, Aline Rimoldi, Carolina Horta Andrade and Fabio Trindade Maranhão Costa

Biomolecules 2021, 11(3), 459; https://doi.org/10.3390/biom11030459 - 19 Mar 2021

Cited by 13 | Viewed by 3924

Abstract

With about 400,000 annual deaths worldwide, malaria remains a public health burden in tropical and subtropical areas, especially in low-income countries. Selection of drug-resistant Plasmodium strains has driven the need to explore novel antimalarial compounds with diverse modes of action. In this context, [...] Read more.

With about 400,000 annual deaths worldwide, malaria remains a public health burden in tropical and subtropical areas, especially in low-income countries. Selection of drug-resistant Plasmodium strains has driven the need to explore novel antimalarial compounds with diverse modes of action. In this context, biodiversity has been widely exploited as a resourceful channel of biologically active compounds, as exemplified by antimalarial drugs such as quinine and artemisinin, derived from natural products. Thus, combining a natural product library and quantitative structure–activity relationship (QSAR)-based virtual screening, we have prioritized genuine and derivative natural compounds with potential antimalarial activity prior to in vitro testing. Experimental validation against cultured chloroquine-sensitive and multi-drug-resistant P. falciparum strains confirmed the potent and selective activity of two sesquiterpene lactones (LDT-597 and LDT-598) identified in silico. Quantitative structure–property relationship (QSPR) models predicted absorption, distribution, metabolism, and excretion (ADME) and physiologically based pharmacokinetic (PBPK) parameters for the most promising compound, showing that it presents good physiologically based pharmacokinetic properties both in rats and humans. Altogether, the in vitro parasite growth inhibition results obtained from in silico screened compounds encourage the use of virtual screening campaigns for identification of promising natural compound-based antimalarial molecules. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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30 pages, 8247 KiB

Open AccessArticle

A Molecular Modeling Approach to Identify Potential Antileishmanial Compounds Against the Cell Division Cycle (cdc)-2-Related Kinase 12 (CRK12) Receptor of Leishmania donovani

by Emmanuel Broni, Samuel K. Kwofie, Seth O. Asiedu, Whelton A. Miller III and Michael D. Wilson

Biomolecules 2021, 11(3), 458; https://doi.org/10.3390/biom11030458 - 18 Mar 2021

Cited by 19 | Viewed by 4804

Abstract

The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania is well known. This illness was included in the list of neglected tropical diseases targeted for elimination by the World Health Organization. However, the increasing evidence of resistance to existing antimonial [...] Read more.

The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania is well known. This illness was included in the list of neglected tropical diseases targeted for elimination by the World Health Organization. However, the increasing evidence of resistance to existing antimonial drugs has made the eradication of the disease difficult to achieve, thus warranting the search for new drug targets. We report here studies that used computational methods to identify inhibitors of receptors from natural products. The cell division cycle-2-related kinase 12 (CRK12) receptor is a plausible drug target against Leishmania donovani. This study modelled the 3D molecular structure of the L. donovani CRK12 (LdCRK12) and screened for small molecules with potential inhibitory activity from African flora. An integrated library of 7722 African natural product-derived compounds and known inhibitors were screened against the LdCRK12 using AutoDock Vina after performing energy minimization with GROMACS 2018. Four natural products, namely sesamin (NANPDB1649), methyl ellagic acid (NANPDB1406), stylopine (NANPDB2581), and sennecicannabine (NANPDB6446) were found to be potential LdCRK12 inhibitory molecules. The molecular docking studies revealed two compounds NANPDB1406 and NANPDB2581 with binding affinities of −9.5 and −9.2 kcal/mol, respectively, against LdCRK12 which were higher than those of the known inhibitors and drugs, including GSK3186899, amphotericin B, miltefosine, and paromomycin. All the four compounds were predicted to have inhibitory constant (Ki) values ranging from 0.108 to 0.587 μM. NANPDB2581, NANPDB1649 and NANPDB1406 were also predicted as antileishmanial with Pa and Pi values of 0.415 and 0.043, 0.391 and 0.052, and 0.351 and 0.071, respectively. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations reinforced their good binding mechanisms. Most compounds were observed to bind in the ATP binding pocket of the kinase domain. Lys488 was predicted as a key residue critical for ligand binding in the ATP binding pocket of the LdCRK12. The molecules were pharmacologically profiled as druglike with inconsequential toxicity. The identified molecules have scaffolds that could form the backbone for fragment-based drug design of novel leishmanicides but warrant further studies to evaluate their therapeutic potential. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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12 pages, 2813 KiB

Open AccessCommunication

In Silico Screening of Natural Products Isolated from Mexican Herbal Medicines against COVID-19

by Nadia A. Rivero-Segura and Juan C. Gomez-Verjan

Biomolecules 2021, 11(2), 216; https://doi.org/10.3390/biom11020216 - 04 Feb 2021

Cited by 29 | Viewed by 4588

Abstract

The COVID-19 pandemic has already taken the lives of more than 2 million people worldwide, causing several political and socio-economic disturbances in our daily life. At the time of publication, there are non-effective pharmacological treatments, and vaccine distribution represents an important challenge for [...] Read more.

The COVID-19 pandemic has already taken the lives of more than 2 million people worldwide, causing several political and socio-economic disturbances in our daily life. At the time of publication, there are non-effective pharmacological treatments, and vaccine distribution represents an important challenge for all countries. In this sense, research for novel molecules becomes essential to develop treatments against the SARS-CoV-2 virus. In this context, Mexican natural products have proven to be quite useful for drug development; therefore, in the present study, we perform an in silico screening of 100 compounds isolated from the most commonly used Mexican plants, against the SARS-CoV-2 virus. As results, we identify ten compounds that meet leadlikeness criteria (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin). According to the docking analysis, only three compounds target the key proteins of SARS-CoV-2 (quercetin, riolozatrione and cichoriin), but only one appears to be safe (cichoriin). ADME (absorption, distribution, metabolism and excretion) properties and the physiologically based pharmacokinetic (PBPK) model show that cichoriin reaches higher lung levels (100 mg/Kg, IV); therefore, it may be considered in developing therapeutic tools. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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13 pages, 2714 KiB

Open AccessArticle

A Computational Approach to Explore the Interaction of Semisynthetic Nitrogenous Heterocyclic Compounds with the SARS-CoV-2 Main Protease

by Alejandro Llanes, Héctor Cruz, Viet D. Nguyen, Oleg V. Larionov and Patricia L. Fernández

Biomolecules 2021, 11(1), 18; https://doi.org/10.3390/biom11010018 - 27 Dec 2020

Cited by 9 | Viewed by 3486

Abstract

In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, numerous attempts have been made to discover new potential antiviral molecules against its causative agent, SARS-CoV-2, many of which focus on its main protease (M^pro). We hereby used two approaches [...] Read more.

In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, numerous attempts have been made to discover new potential antiviral molecules against its causative agent, SARS-CoV-2, many of which focus on its main protease (M^pro). We hereby used two approaches based on molecular docking simulation to explore the interaction of four libraries of semisynthetic nitrogenous heterocyclic compounds with M^pro. Libraries L1 and L2 contain 52 synthetic derivatives of the natural compound 2-propylquinoline, whereas libraries L3 and L4 contain 65 compounds synthesized using the natural compound physostigmine as a precursor. Validation through redocking suggested that the rigid receptor and flexible receptor approaches used for docking were suitable to model the interaction of this type of compounds with the target protein, although the flexible approach seemed to provide a more realistic representation of interactions within the active site. Using empirical energy score thresholds, we selected 58 compounds from the four libraries with the most favorable energy estimates. Globally, favorable estimates were obtained for molecules with two or more substituents, putatively accommodating in three or more subsites within the M^pro active site. Our results pave the way for further experimental evaluation of the selected compounds as potential antiviral agents against SARS-CoV-2. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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16 pages, 5668 KiB

Open AccessArticle

Fragment Library of Natural Products and Compound Databases for Drug Discovery

by Ana L. Chávez-Hernández, Norberto Sánchez-Cruz and José L. Medina-Franco

Biomolecules 2020, 10(11), 1518; https://doi.org/10.3390/biom10111518 - 06 Nov 2020

Cited by 19 | Viewed by 5103

Abstract

Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, [...] Read more.

Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, natural products are excellent substrates of unique substructures for fragment-based drug discovery. To this end, fragment libraries should be incorporated into automated drug design pipelines. However, public fragment libraries based on extensive collections of natural products are still limited. Herein, we report the generation and analysis of a fragment library of natural products derived from a database with more than 400,000 compounds. We also report fragment libraries of a large food chemical database and other compound datasets of interest in drug discovery, including compound libraries relevant for COVID-19 drug discovery. The fragment libraries were characterized in terms of content and diversity. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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11 pages, 2642 KiB

Open AccessArticle

Virtual Screening for Reactive Natural Products and Their Probable Artifacts of Solvolysis and Oxidation

by Tingjun Xu, Weiming Chen, Junhong Zhou, Jingfang Dai, Yingyong Li and Yingli Zhao

Biomolecules 2020, 10(11), 1486; https://doi.org/10.3390/biom10111486 - 27 Oct 2020

Cited by 4 | Viewed by 2040

Abstract

Chemically unstable natural products are prone to show their reactivity in the procedures of extraction, purification, or identification and turn into contaminants as so-called “artifacts”. However, identification of artifacts requires considerable investments in technical equipment, time, and human resources. For revealing these reactive [...] Read more.

Chemically unstable natural products are prone to show their reactivity in the procedures of extraction, purification, or identification and turn into contaminants as so-called “artifacts”. However, identification of artifacts requires considerable investments in technical equipment, time, and human resources. For revealing these reactive natural products and their artifacts by computational approaches, we set up a virtual screening system to seek cases in a biochemical database. The screening system is based on deep learning models of predicting the two main classifications of conversion reactions from natural products to artifacts, namely solvolysis and oxidation. A set of result data was reviewed for checking validity of the screening system, and we screened out a batch of reactive natural products and their probable artifacts. This work provides some insights into the formations of natural product artifacts, and the result data may act as warnings regarding the improper handling of biological matrixes in multicomponent extraction. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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13 pages, 3774 KiB

Open AccessArticle

Assigning the Origin of Microbial Natural Products by Chemical Space Map and Machine Learning

by Alice Capecchi and Jean-Louis Reymond

Biomolecules 2020, 10(10), 1385; https://doi.org/10.3390/biom10101385 - 28 Sep 2020

Cited by 14 | Viewed by 3965

Abstract

Microbial natural products (NPs) are an important source of drugs, however, their structural diversity remains poorly understood. Here we used our recently reported MinHashed Atom Pair fingerprint with diameter of four bonds (MAP4), a fingerprint suitable for molecules across very different sizes, to [...] Read more.

Microbial natural products (NPs) are an important source of drugs, however, their structural diversity remains poorly understood. Here we used our recently reported MinHashed Atom Pair fingerprint with diameter of four bonds (MAP4), a fingerprint suitable for molecules across very different sizes, to analyze the Natural Products Atlas (NPAtlas), a database of 25,523 NPs of bacterial or fungal origin. To visualize NPAtlas by MAP4 similarity, we used the dimensionality reduction method tree map (TMAP). The resulting interactive map organizes molecules by physico-chemical properties and compound families such as peptides and glycosides. Remarkably, the map separates bacterial and fungal NPs from one another, revealing that these two compound families are intrinsically different despite their related biosynthetic pathways. We used these differences to train a machine learning model capable of distinguishing between NPs of bacterial or fungal origin. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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22 pages, 2684 KiB

Open AccessArticle

Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases

by Weronika Wanat, Michał Talma, Błażej Dziuk and Paweł Kafarski

Biomolecules 2020, 10(9), 1319; https://doi.org/10.3390/biom10091319 - 14 Sep 2020

Cited by 1 | Viewed by 2900

Abstract

A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies [...] Read more.

A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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Review

Jump to: Editorial, Research

14 pages, 1324 KiB

Open AccessReview

Cheminformatics to Characterize Pharmacologically Active Natural Products

by José L. Medina-Franco and Fernanda I. Saldívar-González

Biomolecules 2020, 10(11), 1566; https://doi.org/10.3390/biom10111566 - 17 Nov 2020

Cited by 35 | Viewed by 6097

Abstract

Natural products have a significant role in drug discovery. Natural products have distinctive chemical structures that have contributed to identifying and developing drugs for different therapeutic areas. Moreover, natural products are significant sources of inspiration or starting points to develop new therapeutic agents. [...] Read more.

Natural products have a significant role in drug discovery. Natural products have distinctive chemical structures that have contributed to identifying and developing drugs for different therapeutic areas. Moreover, natural products are significant sources of inspiration or starting points to develop new therapeutic agents. Natural products such as peptides and macrocycles, and other compounds with unique features represent attractive sources to address complex diseases. Computational approaches that use chemoinformatics and molecular modeling methods contribute to speed up natural product-based drug discovery. Several research groups have recently used computational methodologies to organize data, interpret results, generate and test hypotheses, filter large chemical databases before the experimental screening, and design experiments. This review discusses a broad range of chemoinformatics applications to support natural product-based drug discovery. We emphasize profiling natural product data sets in terms of diversity; complexity; acid/base; absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties; and fragment analysis. Novel techniques for the visual representation of the chemical space are also discussed. Full article

(This article belongs to the Special Issue Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products)

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Computational Approaches for the Discovery and Development of Pharmacologically Active Natural Products

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