International Journal of Molecular Sciences

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18 pages, 7420 KiB

Open AccessArticle

Potential Antitumor Effect of α-Mangostin against Rat Mammary Gland Tumors Induced by LA7 Cells

by Mohamed Yousif Ibrahim, Najihah Mohd Hashim, Fatima Abdelmutaal Ahmed Omer, Muhammad Salisu Abubakar, Hoyam Adam Mohammed, Suzy Munir Salama and Soher Nagi Jayash

Int. J. Mol. Sci. 2023, 24(12), 10283; https://doi.org/10.3390/ijms241210283 - 17 Jun 2023

Cited by 2 | Viewed by 1985

Abstract

In this study, the chemotherapeutic effect of α-mangostin (AM) was assessed in rats injected with LA7 cells. Rats received AM orally at 30 and 60 mg/kg twice a week for 4 weeks. Cancer biomarkers such as CEA and CA 15-3 were significantly lower [...] Read more.

In this study, the chemotherapeutic effect of α-mangostin (AM) was assessed in rats injected with LA7 cells. Rats received AM orally at 30 and 60 mg/kg twice a week for 4 weeks. Cancer biomarkers such as CEA and CA 15-3 were significantly lower in AM-treated rats. Histopathological evaluations showed that AM protects the rat mammary gland from the carcinogenic effects of LA7 cells. Interestingly, AM decreased lipid peroxidation and increased antioxidant enzymes when compared to the control. Immunohistochemistry results of the untreated rats showed abundant PCNA and fewer p53-positive cells than AM-treated rats. Using the TUNEL test, AM-treated animals had higher apoptotic cell numbers than those untreated. This report revealed that that AM lessened oxidative stress, suppressed proliferation, and minimized LA7-induced mammary carcinogenesis. Therefore, the current study suggests that AM has significant potential for breast cancer treatment. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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16 pages, 4506 KiB

Open AccessArticle

Prediction of Oscillations in Glycolysis in Ethanol-Consuming Erythrocyte-Bioreactors

by Evgeniy Protasov, Michael Martinov, Elena Sinauridze, Victor Vitvitsky and Fazoil Ataullakhanov

Int. J. Mol. Sci. 2023, 24(12), 10124; https://doi.org/10.3390/ijms241210124 - 14 Jun 2023

Viewed by 1118

Abstract

A mathematical model of energy metabolism in erythrocyte-bioreactors loaded with alcohol dehydrogenase and acetaldehyde dehydrogenase was constructed and analyzed. Such erythrocytes can convert ethanol to acetate using intracellular NAD and can therefore be used to treat alcohol intoxication. Analysis of the model revealed [...] Read more.

A mathematical model of energy metabolism in erythrocyte-bioreactors loaded with alcohol dehydrogenase and acetaldehyde dehydrogenase was constructed and analyzed. Such erythrocytes can convert ethanol to acetate using intracellular NAD and can therefore be used to treat alcohol intoxication. Analysis of the model revealed that the rate of ethanol consumption by the erythrocyte-bioreactors increases proportionally to the activity of incorporated ethanol-consuming enzymes until their activity reaches a specific threshold level. When the ethanol-consuming enzyme activity exceeds this threshold, the steady state in the model becomes unstable and the model switches to an oscillation mode caused by the competition between glyceraldehyde phosphate dehydrogenase and ethanol-consuming enzymes for NAD. The amplitude and period of metabolite oscillations first increase with the increase in the activity of the encapsulated enzymes. A further increase in these activities leads to a loss of the glycolysis steady state, and a permanent accumulation of glycolytic intermediates. The oscillation mode and the loss of the steady state can lead to the osmotic destruction of erythrocyte-bioreactors due to an accumulation of intracellular metabolites. Our results demonstrate that the interaction of enzymes encapsulated in erythrocyte-bioreactors with erythrocyte metabolism should be taken into account in order to achieve the optimal efficacy of these bioreactors. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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32 pages, 15994 KiB

Open AccessArticle

Discovery of Chalcone-Based Hybrid Structures as High Affinity and Site-Specific Inhibitors against SARS-CoV-2: A Comprehensive Structural Analysis Based on Various Host-Based and Viral Targets

by Mehdi Valipour, Silvia Di Giacomo, Antonella Di Sotto and Hamid Irannejad

Int. J. Mol. Sci. 2023, 24(10), 8789; https://doi.org/10.3390/ijms24108789 - 15 May 2023

Cited by 3 | Viewed by 1761

Abstract

Previous studies indicated that natural-based chalcones have significant inhibitory effects on the coronavirus enzymes 3CLpro and PLpro as well as modulation of some host-based antiviral targets (HBATs). In this study, a comprehensive computational and structural study was performed to investigate the affinity of [...] Read more.

Previous studies indicated that natural-based chalcones have significant inhibitory effects on the coronavirus enzymes 3CLpro and PLpro as well as modulation of some host-based antiviral targets (HBATs). In this study, a comprehensive computational and structural study was performed to investigate the affinity of our compound library consisting of 757 chalcone-based structures (CHA-1 to CHA-757) for inhibiting the 3CLpro and PLpro enzymes and against twelve selected host-based targets. Our results indicated that CHA-12 (VUF 4819) is the most potent and multi-target inhibitor in our chemical library over all viral and host-based targets. Correspondingly, CHA-384 and its congeners containing ureide moieties were found to be potent and selective 3CLpro inhibitors, and benzotriazole moiety in CHA-37 was found to be a main fragment for inhibiting the 3CLpro and PLpro. Surprisingly, our results indicate that the ureide and sulfonamide moieties are integral fragments for the optimum 3CLpro inhibition while occupying the S1 and S3 subsites, which is fully consistent with recent reports on the site-specific 3CLpro inhibitors. Finding the multi-target inhibitor CHA-12, previously reported as an LTD4 antagonist for the treatment of inflammatory pulmonary diseases, prompted us to suggest it as a concomitant agent for relieving respiratory symptoms and suppressing COVID-19 infection. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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26 pages, 44898 KiB

Open AccessArticle

Novel Functionalized Spiro [Indoline-3,5′-pyrroline]-2,2′dione Derivatives: Synthesis, Characterization, Drug-Likeness, ADME, and Anticancer Potential

by Mohd Asif, Sahir Sultan Alvi, Tazeen Azaz, Abdul Rahman Khan, Bhoopendra Tiwari, Bilal Bin Hafeez and Malik Nasibullah

Int. J. Mol. Sci. 2023, 24(8), 7336; https://doi.org/10.3390/ijms24087336 - 15 Apr 2023

Cited by 8 | Viewed by 2233

Abstract

A highly stereo-selective, one-pot, multicomponent method was chosen to synthesize the novel functionalized 1, 3-cycloaddition spirooxindoles (SOXs) (4a–4h). Synthesized SOXs were analyzed for their drug-likeness and ADME parameters and screened for their anticancer activity. Our molecular docking analysis revealed [...] Read more.

A highly stereo-selective, one-pot, multicomponent method was chosen to synthesize the novel functionalized 1, 3-cycloaddition spirooxindoles (SOXs) (4a–4h). Synthesized SOXs were analyzed for their drug-likeness and ADME parameters and screened for their anticancer activity. Our molecular docking analysis revealed that among all derivatives of SOXs (4a–4h), 4a has a substantial binding affinity (∆G) −6.65, −6.55, −8.73, and −7.27 Kcal/mol with CD-44, EGFR, AKR1D1, and HER-2, respectively. A functional study demonstrated that SOX 4a has a substantial impact on human cancer cell phenotypes exhibiting abnormality in cytoplasmic and nuclear architecture as well as granule formation leading to cell death. SOX 4a treatment robustly induced reactive oxygen species (ROS) generation in cancer cells as observed by enhanced DCFH-DA signals. Overall, our results suggest that SOX (4a) targets CD-44, EGFR, AKR1D1, and HER-2 and induces ROS generation in cancer cells. We conclude that SOX (4a) could be explored as a potential chemotherapeutic molecule against various cancers in appropriate pre-clinical in vitro and in vivo model systems. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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16 pages, 3430 KiB

Open AccessArticle

Multiscale Analysis and Validation of Effective Drug Combinations Targeting Driver KRAS Mutations in Non-Small Cell Lung Cancer

by Liana Bruggemann, Zackary Falls, William Mangione, Stanley A. Schwartz, Sebastiano Battaglia, Ravikumar Aalinkeel, Supriya D. Mahajan and Ram Samudrala

Int. J. Mol. Sci. 2023, 24(2), 997; https://doi.org/10.3390/ijms24020997 - 5 Jan 2023

Cited by 2 | Viewed by 3591

Abstract

Pharmacogenomics is a rapidly growing field with the goal of providing personalized care to every patient. Previously, we developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform for multiscale therapeutic discovery to screen optimal compounds for any indication/disease by performing analytics on [...] Read more.

Pharmacogenomics is a rapidly growing field with the goal of providing personalized care to every patient. Previously, we developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform for multiscale therapeutic discovery to screen optimal compounds for any indication/disease by performing analytics on their interactions using large protein libraries. We implemented a comprehensive precision medicine drug discovery pipeline within the CANDO platform to determine which drugs are most likely to be effective against mutant phenotypes of non-small cell lung cancer (NSCLC) based on the supposition that drugs with similar interaction profiles (or signatures) will have similar behavior and therefore show synergistic effects. CANDO predicted that osimertinib, an EGFR inhibitor, is most likely to synergize with four KRAS inhibitors.Validation studies with cellular toxicity assays confirmed that osimertinib in combination with ARS-1620, a KRAS G12C inhibitor, and BAY-293, a pan-KRAS inhibitor, showed a synergistic effect on decreasing cellular proliferation by acting on mutant KRAS. Gene expression studies revealed that MAPK expression is strongly correlated with decreased cellular proliferation following treatment with KRAS inhibitor BAY-293, but not treatment with ARS-1620 or osimertinib. These results indicate that our precision medicine pipeline may be used to identify compounds capable of synergizing with inhibitors of KRAS G12C, and to assess their likelihood of becoming drugs by understanding their behavior at the proteomic/interactomic scales. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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22 pages, 3239 KiB

Open AccessArticle

Structural and Spectroscopic Properties of Isoconazole and Bifonazole—Experimental and Theoretical Studies

by Beata Drabińska, Katarzyna Dettlaff, Tomasz Ratajczak, Kacper Kossakowski, Marcin K. Chmielewski, Judyta Cielecka-Piontek and Jacek Kujawski

Int. J. Mol. Sci. 2023, 24(1), 520; https://doi.org/10.3390/ijms24010520 - 28 Dec 2022

Cited by 1 | Viewed by 1789

Abstract

The paper compares the experimental FT-IR, UV-vis, and ¹H NMR spectra of isoconazole and bifonazole with the density functional theory (DFT) calculations using different functionals. The results were compared with previously reported data related to their analogue, posaconazole. The analysis of calculated [...] Read more.

The paper compares the experimental FT-IR, UV-vis, and ¹H NMR spectra of isoconazole and bifonazole with the density functional theory (DFT) calculations using different functionals. The results were compared with previously reported data related to their analogue, posaconazole. The analysis of calculated IR spectra with use of CAM-B3LYP (isoconazole) or B3LYP (bifonazole) functionals shows good accordance with the experimental IR spectrum. The best compatibility between the experimental and theoretical UV spectra was observed with the use of B3LYP or wB97XD functionals for isoconazole or bifonazole, respectively. The reason for the difference in the UV-vis spectra of isoconazole and bifonazole was discussed based on linear response time-dependent DFT and natural bond orbital methods. The calculated ¹H NMR spectrum shows that the DFT formalism, particularly the B3LYP functional, give an accurate description of the isoconazole and bifonazole chemical shifts. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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16 pages, 2756 KiB

Open AccessArticle

Characterisation of the Molecular Mechanism of Permeation of the Prodrug Me-5ALA across the Human Stratum Corneum Using Molecular Dynamics Simulations

by Janonna Kadyrov, Lanie Ruiz-Perez, Heather A. E. Benson and Ricardo L. Mancera

Int. J. Mol. Sci. 2022, 23(24), 16001; https://doi.org/10.3390/ijms232416001 - 15 Dec 2022

Viewed by 1831

Abstract

The barrier imposed by the outer layer of the skin, the stratum corneum, creates an almost impermeable environment for exogenous substances. Few lipophilic drugs with low molecular mass can passively diffuse through this layer, highlighting the need to develop methods to enable [...] Read more.

The barrier imposed by the outer layer of the skin, the stratum corneum, creates an almost impermeable environment for exogenous substances. Few lipophilic drugs with low molecular mass can passively diffuse through this layer, highlighting the need to develop methods to enable the delivery of more drugs via the transdermal route. The prodrug approach involves modifying the structure of a drug molecule to enhance its permeability across the skin, but it is often difficult to predict how exactly changes in chemical structure affect permeation. This study uses molecular dynamics simulations to predict permeability values and adequately characterise the molecular mechanism of permeation of the prodrugs Me-5ALA and its parent compound 5ALA across a molecular model of the lipid bilayers of the human stratum corneum. The influence of increased hydrophobicity in Me-5ALA on its permeation revealed a reduction in hydrogen bonding capability that enables it to interact more favourably with the hydrophobic region of the bilayer and diffuse at a faster rate with less resistance, thus making it a better permeant compared to its more hydrophilic parent compound. This molecular simulation approach offers a promising route for the rational design of drug molecules that can permeate effectively across the stratum corneum. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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16 pages, 3221 KiB

Open AccessArticle

Escherichia coli as a New Platform for the Fast Production of Vault-like Nanoparticles: An Optimized Protocol

by Roger Fernández, Aida Carreño, Rosa Mendoza, Antoni Benito, Neus Ferrer-Miralles, María Virtudes Céspedes and José Luis Corchero

Int. J. Mol. Sci. 2022, 23(24), 15543; https://doi.org/10.3390/ijms232415543 - 8 Dec 2022

Cited by 2 | Viewed by 2259

Abstract

Vaults are protein nanoparticles that are found in almost all eukaryotic cells but are absent in prokaryotic ones. Due to their properties (nanometric size, biodegradability, biocompatibility, and lack of immunogenicity), vaults show enormous potential as a bio-inspired, self-assembled drug-delivery system (DDS). Vault architecture [...] Read more.

Vaults are protein nanoparticles that are found in almost all eukaryotic cells but are absent in prokaryotic ones. Due to their properties (nanometric size, biodegradability, biocompatibility, and lack of immunogenicity), vaults show enormous potential as a bio-inspired, self-assembled drug-delivery system (DDS). Vault architecture is directed by self-assembly of the “major vault protein” (MVP), the main component of this nanoparticle. Recombinant expression (in different eukaryotic systems) of the MVP resulted in the formation of nanoparticles that were indistinguishable from native vaults. Nowadays, recombinant vaults for different applications are routinely produced in insect cells and purified by successive ultracentrifugations, which are both tedious and time-consuming strategies. To offer cost-efficient and faster protocols for nanoparticle production, we propose the production of vault-like nanoparticles in Escherichia coli cells, which are still one of the most widely used prokaryotic cell factories for recombinant protein production. The strategy proposed allowed for the spontaneous encapsulation of the engineered cargo protein within the self-assembled vault-like nanoparticles by simply mixing the clarified lysates of the producing cells. Combined with well-established affinity chromatography purification methods, our approach contains faster, cost-efficient procedures for biofabrication in a well-known microbial cell factory and the purification of “ready-to-use” loaded protein nanoparticles, thereby opening the way to faster and easier engineering and production of vault-based DDSs. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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15 pages, 4835 KiB

Open AccessArticle

Structural Basis of Cysteine Ligase MshC Inhibition by Cysteinyl-Sulfonamides

by Luping Pang, Stijn Lenders, Evgenii M. Osipov, Stephen D. Weeks, Jef Rozenski, Tatiana Piller, Davie Cappoen, Sergei V. Strelkov and Arthur Van Aerschot

Int. J. Mol. Sci. 2022, 23(23), 15095; https://doi.org/10.3390/ijms232315095 - 1 Dec 2022

Cited by 1 | Viewed by 1719

Abstract

Mycothiol (MSH), the major cellular thiol in Mycobacterium tuberculosis (Mtb), plays an essential role in the resistance of Mtb to various antibiotics and oxidative stresses. MshC catalyzes the ATP-dependent ligation of 1-O-(2-amino-2-deoxy-α-d-glucopyranosyl)-d-myo-inositol (GlcN-Ins) with l [...] Read more.

Mycothiol (MSH), the major cellular thiol in Mycobacterium tuberculosis (Mtb), plays an essential role in the resistance of Mtb to various antibiotics and oxidative stresses. MshC catalyzes the ATP-dependent ligation of 1-O-(2-amino-2-deoxy-α-d-glucopyranosyl)-d-myo-inositol (GlcN-Ins) with l-cysteine (l-Cys) to form l-Cys-GlcN-Ins, the penultimate step in MSH biosynthesis. The inhibition of MshC is lethal to Mtb. In the present study, five new cysteinyl-sulfonamides were synthesized, and their binding affinity with MshC was evaluated using a thermal shift assay. Two of them bind the target with EC₅₀ values of 219 and 231 µM. Crystal structures of full-length MshC in complex with these two compounds showed that they were bound in the catalytic site of MshC, inducing dramatic conformational changes of the catalytic site compared to the apo form. In particular, the observed closure of the KMSKS loop was not detected in the published cysteinyl-sulfamoyl adenosine-bound structure, the latter likely due to trypsin treatment. Despite the confirmed binding to MshC, the compounds did not suppress Mtb culture growth, which might be explained by the lack of adequate cellular uptake. Taken together, these novel cysteinyl-sulfonamide MshC inhibitors and newly reported full-length apo and ligand-bound MshC structures provide a promising starting point for the further development of novel anti-tubercular drugs targeting MshC. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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16 pages, 3703 KiB

Open AccessArticle

Bergamottin and PAP-1 Induced ACE2 Degradation to Alleviate Infection of SARS-CoV-2

by Mengjia Li, Yongzheng Zhang, Amir Zeb, Yang Wu and Lufeng Cheng

Int. J. Mol. Sci. 2022, 23(20), 12565; https://doi.org/10.3390/ijms232012565 - 19 Oct 2022

Cited by 4 | Viewed by 1642

Abstract

Angiotensin-converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. However, inhibitors such as PAP-1 and bergamottin have been discovered; both of them can preferentially bind to ACE2, prevent RBD Spike S protein from [...] Read more.

Angiotensin-converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. However, inhibitors such as PAP-1 and bergamottin have been discovered; both of them can preferentially bind to ACE2, prevent RBD Spike S protein from binding to ACE2, and reduce the binding sites for RBD Spike S protein. In addition, we investigated the binding energy of PAP-1 and bergamottin with ACE2 through molecular docking with bio-layer interferometry (BLI) and found relatively high binding affinity (KD = 48.5 nM, 53.1 nM) between the PAP-1 and bergamottin groups. In addition, the nanomolar fraction had no effect on growth of the AT-II cell, but 150 µM PAP-1 and 75 µM bergamottin inhibited the proliferation of AT-II cells in vitro by 75% and 68%, respectively. Meanwhile, they significantly reduced ACE2 mRNA and proteins by 67%, 58% and 55%, 41%, respectively. These results indicate that psoralen compounds PAP-1 and bergamottin binding to ACE2 protein could be further developed in the fight against COVID-19 infection during the current pandemic. However, attention should be paid to the damage to human alveolar type II epithelial cells. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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20 pages, 6641 KiB

Open AccessArticle

Ligand-Enhanced Negative Images Optimized for Docking Rescoring

by Sami T. Kurkinen, Jukka V. Lehtonen, Olli T. Pentikäinen and Pekka A. Postila

Int. J. Mol. Sci. 2022, 23(14), 7871; https://doi.org/10.3390/ijms23147871 - 17 Jul 2022

Cited by 1 | Viewed by 2128

Abstract

Despite the pivotal role of molecular docking in modern drug discovery, the default docking scoring functions often fail to recognize active ligands in virtual screening campaigns. Negative image-based rescoring improves docking enrichment by comparing the shape/electrostatic potential (ESP) of the flexible docking poses [...] Read more.

Despite the pivotal role of molecular docking in modern drug discovery, the default docking scoring functions often fail to recognize active ligands in virtual screening campaigns. Negative image-based rescoring improves docking enrichment by comparing the shape/electrostatic potential (ESP) of the flexible docking poses against the target protein’s inverted cavity volume. By optimizing these negative image-based (NIB) models using a greedy search, the docking rescoring yield can be improved massively and consistently. Here, a fundamental modification is implemented to this shape-focused pharmacophore modelling approach—actual ligand 3D coordinates are incorporated into the NIB models for the optimization. This hybrid approach, labelled as ligand-enhanced brute-force negative image-based optimization (LBR-NiB), takes the best from both worlds, i.e., the all-roundedness of the NIB models and the difficult to emulate atomic arrangements of actual protein-bound small-molecule ligands. Thorough benchmarking, focused on proinflammatory targets, shows that the LBR-NiB routinely improves the docking enrichment over prior iterations of the R-NiB methodology. This boost can be massive, if the added ligand information provides truly essential binding information that was lacking or completely missing from the cavity-based NIB model. On a practical level, the results indicate that the LBR-NiB typically works well when the added ligand 3D data originates from a high-quality source, such as X-ray crystallography, and, yet, the NIB model compositions can also sometimes be improved by fusing into them, for example, with flexibly docked solvent molecules. In short, the study demonstrates that the protein-bound ligands can be used to improve the shape/ESP features of the negative images for effective docking rescoring use in virtual screening. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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Review

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22 pages, 2451 KiB

Open AccessReview

Physiologically Based Pharmacokinetic Modeling of Nanoparticle Biodistribution: A Review of Existing Models, Simulation Software, and Data Analysis Tools

by Elena O. Kutumova, Ilya R. Akberdin, Ilya N. Kiselev, Ruslan N. Sharipov, Vera S. Egorova, Anastasiia O. Syrocheva, Alessandro Parodi, Andrey A. Zamyatnin, Jr. and Fedor A. Kolpakov

Int. J. Mol. Sci. 2022, 23(20), 12560; https://doi.org/10.3390/ijms232012560 - 19 Oct 2022

Cited by 8 | Viewed by 3311

Abstract

Cancer treatment and pharmaceutical development require targeted treatment and less toxic therapeutic intervention to achieve real progress against this disease. In this scenario, nanomedicine emerged as a reliable tool to improve drug pharmacokinetics and to translate to the clinical biologics based on large [...] Read more.

Cancer treatment and pharmaceutical development require targeted treatment and less toxic therapeutic intervention to achieve real progress against this disease. In this scenario, nanomedicine emerged as a reliable tool to improve drug pharmacokinetics and to translate to the clinical biologics based on large molecules. However, the ability of our body to recognize foreign objects together with carrier transport heterogeneity derived from the combination of particle physical and chemical properties, payload and surface modification, make the designing of effective carriers very difficult. In this scenario, physiologically based pharmacokinetic modeling can help to design the particles and eventually predict their ability to reach the target and treat the tumor. This effort is performed by scientists with specific expertise and skills and familiarity with artificial intelligence tools such as advanced software that are not usually in the “cords” of traditional medical or material researchers. The goal of this review was to highlight the advantages that computational modeling could provide to nanomedicine and bring together scientists with different background by portraying in the most simple way the work of computational developers through the description of the tools that they use to predict nanoparticle transport and tumor targeting in our body. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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24 pages, 13844 KiB

Open AccessReview

Poisonous Piperidine Plants and the Biodiversity of Norditerpenoid Alkaloids for Leads in Drug Discovery: Experimental Aspects

by Ashraf M. A. Qasem, Michael G. Rowan and Ian S. Blagbrough

Int. J. Mol. Sci. 2022, 23(20), 12128; https://doi.org/10.3390/ijms232012128 - 12 Oct 2022

Cited by 3 | Viewed by 1897

Abstract

There are famous examples of simple (e.g., hemlock, Conium maculatum L.) and complex (e.g., opium poppy, Papaver somniferum L., Papaveraceae) piperidine-alkaloid-containing plants. Many of these are highly poisonous, whilst pepper is well-known gastronomically, and several substituted piperidine alkaloids are therapeutically beneficial as a [...] Read more.

There are famous examples of simple (e.g., hemlock, Conium maculatum L.) and complex (e.g., opium poppy, Papaver somniferum L., Papaveraceae) piperidine-alkaloid-containing plants. Many of these are highly poisonous, whilst pepper is well-known gastronomically, and several substituted piperidine alkaloids are therapeutically beneficial as a function of dose and mode of action. This review covers the taxonomy of the genera Aconitum, Delphinium, and the controversial Consolida. As part of studying the biodiversity of norditerpenoid alkaloids (NDAS), the majority of which possess an N-ethyl group, we also quantified the fragment occurrence count in the SciFinder database for NDA skeletons. The wide range of NDA biodiversity is also captured in a review of over 100 recently reported isolated alkaloids. Ring A substitution at position 1 is important to determine the NDA skeleton conformation. In this overview of naturally occurring highly oxygenated NDAs from traditional Aconitum and Delphinium plants, consideration is given to functional effect and to real functional evidence. Their high potential biological activity makes them useful candidate molecules for further investigation as lead compounds in the development of selective drugs. Full article

(This article belongs to the Special Issue Developments in Drug Discovery: Computational and Experimental Aspects)

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