Vismodegib anticancer drug: Analyzing electronic and structural features and examining biological activities

Vismodegib (Vis) is an anticancer drug, in which its electronic and structural features were examined in this work. To this aim, the chlorine atoms of original Vis model were substituted by other fluorine, bromine, and iodine halogen atoms yielding F-Vis, Br-Vis, and I-Vis in addition to the original Cl-Vis model. The models were optimized by performing quantum chemical calculations and their interactions with the smoothened (SMO) target were examined by performing molecular docking simulations. The results indicated that the stabilized structures of halogenated Vis models were achievable and their features indicated the dominant role of halogen atoms for their participation in interactions with other substances. Based on the obtained results, Br-Vis model was seen suitable for participating in interaction with the SMO target even better than the original Vis model. The hypothesis of this work was affirmed by employing the in silico approach for analyzing the features of singular ligands and for evaluating their biological functions.

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Metal Complexes Derived of Diosmin with Biological Activities in vitro

Journal of Materials Science Research ◽

10.5539/jmsr.v9n1p10 ◽

2019 ◽

Vol 9 (1) ◽

pp. 10

Author(s):

Maéli M. F. Civa ◽

Dirceu G. de Souza ◽

Renata G. Silva ◽

Dayany da S. A. Maciel ◽

Ricardo L. Tranquilin ◽

...

Keyword(s):

Metal Complexes ◽

Biological Activities ◽

Coordination Complexes ◽

Human Leukemia ◽

Human Leukemia Cells ◽

Ft Ir ◽

Xrd Techniques ◽

Better Than

The coordination of metal ions with flavonoids is applied to improve its pharmacological properties. To evaluate the role of ions on diosmin new complexes with Fe(II), Cu(II) and Co(II) ions were synthetized and characterized by UV, FT-IR and XRD techniques and surface morphology by SEM. The biological activity of coordination complexes in vitro, the antioxidant (ABTS), antibacterial (disc diffusion and MIC) and antitumoral activities (MTT) were analyzed. Diosmin when reacting with Fe(II) at 50ºC loses the sugar molecule becoming diosmetin (D) coordinated at 1D:1Fe ratio. In presence of Cu(II) and Co(II) at the same conditions besides losing the sugar, diosmin loses the methyl group at C4’ and H at C3’, producing a new ligand and complexes at 1D:2Cu or Co ratio, to produce DCu and DCo, respectively. The coordination of Cu and Fe improve the antioxidant activity of diosmin. DCo was the only presented antibacterial activity. Additionally, a specific antitumor effect of diosmin and metal complexes upon human leukemia cells was demonstrated, suggesting an immune regulatory action. The anti-melanoma activity of DCo is 10 times better than diosmin. Metal coordination could be used to improve drug activity and to give direction to a new possibility of clinical use for diosmin.

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Can machine learning consistently improve the scoring power of classical scoring functions? Insights into the role of machine learning in scoring functions

Briefings in Bioinformatics ◽

10.1093/bib/bbz173 ◽

2020 ◽

Cited By ~ 4

Author(s):

Chao Shen ◽

Ye Hu ◽

Zhe Wang ◽

Xujun Zhang ◽

Haiyang Zhong ◽

...

Keyword(s):

Machine Learning ◽

Biological Activities ◽

Gradient Boosting ◽

Linear Regression Method ◽

Scoring Functions ◽

Binding Affinities ◽

Training Set ◽

Sequence Similarities ◽

Better Than

Abstract How to accurately estimate protein–ligand binding affinity remains a key challenge in computer-aided drug design (CADD). In many cases, it has been shown that the binding affinities predicted by classical scoring functions (SFs) cannot correlate well with experimentally measured biological activities. In the past few years, machine learning (ML)-based SFs have gradually emerged as potential alternatives and outperformed classical SFs in a series of studies. In this study, to better recognize the potential of classical SFs, we have conducted a comparative assessment of 25 commonly used SFs. Accordingly, the scoring power was systematically estimated by using the state-of-the-art ML methods that replaced the original multiple linear regression method to refit individual energy terms. The results show that the newly-developed ML-based SFs consistently performed better than classical ones. In particular, gradient boosting decision tree (GBDT) and random forest (RF) achieved the best predictions in most cases. The newly-developed ML-based SFs were also tested on another benchmark modified from PDBbind v2007, and the impacts of structural and sequence similarities were evaluated. The results indicated that the superiority of the ML-based SFs could be fully guaranteed when sufficient similar targets were contained in the training set. Moreover, the effect of the combinations of features from multiple SFs was explored, and the results indicated that combining NNscore2.0 with one to four other classical SFs could yield the best scoring power. However, it was not applicable to derive a generic target-specific SF or SF combination.

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Structural analysis of an iron-assisted carbon monolayer for delivery of 2-thiouracil

Main Group Chemistry ◽

10.3233/mgc-210079 ◽

2021 ◽

pp. 1-9

Author(s):

Azar Asgari Pari ◽

Mohammad Yousefi ◽

Susan Samadi ◽

Mohammad Reza Allahgholi Ghasri ◽

Maryam Bikhof Torbati

Keyword(s):

Drug Delivery ◽

Molecular Orbital ◽

Density Functional ◽

Dominant Role ◽

Structural Features ◽

Coupling Constants ◽

Functional Theory ◽

Quadrupole Coupling ◽

Atomic Descriptors

An idea of employing an iron-assisted carbon (FeC) monolayer for delivery of 2-thiouracil (2TU) was examined in this work by analyzing structural features for singular and bimolecular models. Density functional theory (DFT) calculations were performed for optimizing the structures and evaluating molecular and atomic descriptors for analyzing the models systems. Two bimolecular models were obtained assigning by S-FeC and O-FeC models, in which each of S and O atom of 2TU was relaxed towards the Fe region of FeC surface in the mentioned models, respectively. The results indicated that both models were achievable with slightly more favorability for formation of S-FeC model. The obtained molecular orbital properties revealed the dominant role of FeC monolayer for managing future interactions of attached 2TU, which is indeed a major role for employing nanomaterials for targeted drug delivery purposes. In addition to energies and molecular orbital features, atomic quadrupole coupling constants indicated the benefit of employing FeC monolayer for drug delivery of 2TU.

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MARTs and MARylation in the Cytosol: Biological Functions, Mechanisms of Action, and Therapeutic Potential

Cells ◽

10.3390/cells10020313 ◽

2021 ◽

Vol 10 (2) ◽

pp. 313

Author(s):

Sridevi Challa ◽

MiKayla S. Stokes ◽

W. Lee Kraus

Keyword(s):

Stress Responses ◽

Molecular Mechanisms ◽

Neuronal Development ◽

New Technologies ◽

Therapeutic Potential ◽

Structural Features ◽

Cellular Transport ◽

Biological Functions ◽

Post Translational Modification

Mono(ADP-ribosyl)ation (MARylation) is a regulatory post-translational modification of proteins that controls their functions through a variety of mechanisms. MARylation is catalyzed by mono(ADP-ribosyl) transferase (MART) enzymes, a subclass of the poly(ADP-ribosyl) polymerase (PARP) family of enzymes. Although the role of PARPs and poly(ADP-ribosyl)ation (PARylation) in cellular pathways, such as DNA repair and transcription, is well studied, the role of MARylation and MARTs (i.e., the PARP ‘monoenzymes’) are not well understood. Moreover, compared to PARPs, the development of MART-targeted therapeutics is in its infancy. Recent studies are beginning to shed light on the structural features, catalytic targets, and biological functions of MARTs. The development of new technologies to study MARTs have uncovered essential roles for these enzymes in the regulation of cellular processes, such as RNA metabolism, cellular transport, focal adhesion, and stress responses. These insights have increased our understanding of the biological functions of MARTs in cancers, neuronal development, and immune responses. Furthermore, several novel inhibitors of MARTs have been developed and are nearing clinical utility. In this review, we summarize the biological functions and molecular mechanisms of MARTs and MARylation, as well as recent advances in technology that have enabled detection and inhibition of their activity. We emphasize PARP-7, which is at the forefront of the MART subfamily with respect to understanding its biological roles and the development of therapeutically useful inhibitors. Collectively, the available studies reveal a growing understanding of the biochemistry, chemical biology, physiology, and pathology of MARTs.

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Polyketide mimetics yield structural and mechanistic insights into product template domain function in nonreducing polyketide synthases

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1609001114 ◽

2017 ◽

Vol 114 (21) ◽

pp. E4142-E4148 ◽

Cited By ~ 10

Author(s):

Jesus F. Barajas ◽

Gaurav Shakya ◽

Gabriel Moreno ◽

Heriberto Rivera ◽

David R. Jackson ◽

...

Keyword(s):

Active Site ◽

Structural Features ◽

Polyketide Synthases ◽

Catalytic Cycle ◽

Docking Simulations ◽

Close Proximity ◽

Coordinated Water ◽

Cocrystal Structure

Product template (PT) domains from fungal nonreducing polyketide synthases (NR-PKSs) are responsible for controlling the aldol cyclizations of poly-β-ketone intermediates assembled during the catalytic cycle. Our ability to understand the high regioselective control that PT domains exert is hindered by the inaccessibility of intrinsically unstable poly-β-ketones for in vitro studies. We describe here the crystallographic application of “atom replacement” mimetics in which isoxazole rings linked by thioethers mimic the alternating sites of carbonyls in the poly-β-ketone intermediates. We report the 1.8-Å cocrystal structure of the PksA PT domain from aflatoxin biosynthesis with a heptaketide mimetic tethered to a stably modified 4′-phosphopantetheine, which provides important empirical evidence for a previously proposed mechanism of PT-catalyzed cyclization. Key observations support the proposed deprotonation at C4 of the nascent polyketide by the catalytic His1345 and the role of a protein-coordinated water network to selectively activate the C9 carbonyl for nucleophilic addition. The importance of the 4′-phosphate at the distal end of the pantetheine arm is demonstrated to both facilitate delivery of the heptaketide mimetic deep into the PT active site and anchor one end of this linear array to precisely meter C4 into close proximity to the catalytic His1345. Additional structural features, docking simulations, and mutational experiments characterize protein–substrate mimic interactions, which likely play roles in orienting and stabilizing interactions during the native multistep catalytic cycle. These findings afford a view of a polyketide “atom-replaced” mimetic in a NR-PKS active site that could prove general for other PKS domains.

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Isoflavonoids — an overview of their biological activities and potential health benefits

Interdisciplinary Toxicology ◽

10.2478/v10102-009-0021-3 ◽

2009 ◽

Vol 2 (4) ◽

pp. 211-218 ◽

Cited By ~ 43

Author(s):

Eva Miadoková

Keyword(s):

Secondary Metabolites ◽

Skin Diseases ◽

Biological Activities ◽

Health Benefits ◽

Plant Secondary Metabolites ◽

Epidemiologic Studies ◽

Biological Functions ◽

Potential Health ◽

Health Promoting

Isoflavonoids — an overview of their biological activities and potential health benefitsThere are many biological activities attributed to isoflavonoids. The majority of them could be beneficial and some of them may be detrimental, depending on specific circumstances. Isoflavonoids play an important role in human nutrition as health promoting natural chemicals. They belong to plant secondary metabolites that mediate diverse biological functions through numerous pathways. They are structurally similar to estrogens, exerting both estrogenic and antiestrogenic properties in various tissues. The results of epidemiologic studies exploring the role of isoflavonoids in human health have been inconclusive. Some studies support the notion of a protective effect of their consumption in immunomodulation, cognition, risk reduction of certain cancers, cardiovascular and skin diseases, osteoporosis and obesity, as well as relief of menopausal symptoms. Other studies failed to demonstrate any effects.

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Proton-Sensing GPCRs in Health and Disease

Cells ◽

10.3390/cells10082050 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2050

Author(s):

Marco Sisignano ◽

Michael J. M. Fischer ◽

Gerd Geisslinger

Keyword(s):

Intestinal Inflammation ◽

Tumor Biology ◽

Structural Features ◽

G Protein Coupled Receptors ◽

Biological Functions ◽

Future Studies ◽

Health And Disease ◽

G Protein Coupled ◽

Potential Use

The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies.

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Acetylenic Aquatic Anticancer Agents and Related Compounds

Natural Product Communications ◽

10.1177/1934578x0600100914 ◽

2006 ◽

Vol 1 (9) ◽

pp. 1934578X0600100 ◽

Cited By ~ 1

Author(s):

Valery M Dembitsky ◽

Dmitri O Levitsky ◽

Tatyana A Gloriozova ◽

Vladimir V Poroikov

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Aquatic Organisms ◽

Structural Features ◽

Biologically Active ◽

Terrestrial Plants ◽

Anticancer Activities ◽

Pharmaceutical Industries ◽

New Applications

Although acetylenes are common as components of terrestrial plants, it is only within the last 30 years that biologically active polyacetylenes having unusual structural features have been reported from aquatic organisms: cyanobacteria, algae, fungi, invertebrates, and other sources. Naturally occurring aquatic acetylenes are of particular interest since many of them display important biological activities and possess antitumor, antibacterial, antimicrobial, antifouling, antifungal, pesticidal, phototoxic, HIV inhibitory, and immuno-suppressive properties. There is no doubt that they are of great interest, especially for the medicinal and/or pharmaceutical industries. This review presents structures and describes cytotoxic and anticancer activities of more than 230 acetylenic metabolites isolated from aquatic organisms. With the computer program PASS some additional biological activities are also predicted, which point toward possible new applications of these compounds. This review emphasizes the role of aquatic acetylenic compounds as an important source of leads for drug discovery.

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Data-Driven Exploration of Selectivity and Off-Target Activities of Designated Chemical Probes

Molecules ◽

10.3390/molecules23102434 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2434 ◽

Cited By ~ 4

Author(s):

Filip Miljković ◽

Jürgen Bajorath

Keyword(s):

Small Molecules ◽

High Selectivity ◽

Data Driven ◽

Biological Functions ◽

Chemical Probes ◽

Primary Target ◽

Activity Data ◽

Better Than ◽

Key Questions

Chemical probes are of central relevance for chemical biology. To unambiguously explore the role of target proteins in triggering or mediating biological functions, small molecules used as probes should ideally be target-specific; at least, they should have sufficiently high selectivity for a primary target. We present a thorough analysis of currently available activity data for designated chemical probes to address several key questions: How well defined are chemical probes? What is their level of selectivity? Is there evidence for additional activities? Are some probes “better” than others? Therefore, highly curated chemical probes were collected and their selectivity was analyzed on the basis of publicly available compound activity data. Different selectivity patterns were observed, which distinguished designated high-quality probes.

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Examining the Role of Language in Play Among Children With and Without Developmental Disabilities

Language Speech and Hearing Services in Schools ◽

10.1044/2020_lshss-19-00084 ◽

2020 ◽

Vol 51 (3) ◽

pp. 795-806 ◽

Cited By ~ 1

Author(s):

Elizabeth J. Short ◽

Rachael Cooper Schindler ◽

Rita Obeid ◽

Maia M. Noeder ◽

Laura E. Hlavaty ◽

...

Keyword(s):

Developmental Disabilities ◽

Autism Spectrum ◽

Free Play ◽

Group Differences ◽

Typically Developing ◽

Play Skills ◽

Critical Aspect ◽

Hyperactivity Disorder ◽

Better Than

Purpose Play is a critical aspect of children's development, and researchers have long argued that symbolic deficits in play may be diagnostic of developmental disabilities. This study examined whether deficits in play emerge as a function of developmental disabilities and whether our perceptions of play are colored by differences in language and behavioral presentations. Method Ninety-three children participated in this study (typically developing [TD]; n = 23, developmental language disorders [DLD]; n = 24, attention-deficit/hyperactivity disorder [ADHD]; n = 26, and autism spectrum disorder [ASD]; n = 20). Children were videotaped engaging in free-play. Children's symbolic play (imagination, organization, elaboration, and comfort) was scored under conditions of both audible language and no audible language to assess diagnostic group differences in play and whether audible language impacted raters' perception of play. Results Significant differences in play were evident across diagnostic groups. The presence of language did not alter play ratings for the TD group, but differences were found among the other diagnostic groups. When language was audible, children with DLD and ASD (but not ADHD) were scored poorly on play compared to their TD peers. When language was not audible, children with DLD were perceived to play better than when language was audible. Conversely, children with ADHD showed organizational deficits when language was not available to support their play. Finally, children with ASD demonstrated poor play performance regardless of whether language was audible or not. Conclusions Language affects our understanding of play skills in some young children. Parents, researchers, and clinicians must be careful not to underestimate or overestimate play based on language presentation. Differential skills in language have the potential to unduly influence our perceptions of play for children with developmental disabilities.

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