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Journal of Chemical Information and... Mar 2023Cytochrome P450 enzymes aid in the elimination of a preponderance of small molecule drugs, but can generate reactive metabolites that may adversely react with protein...
Cytochrome P450 enzymes aid in the elimination of a preponderance of small molecule drugs, but can generate reactive metabolites that may adversely react with protein and DNA and prompt drug candidate attrition or market withdrawal. Previously developed models help understand how these enzymes modify molecule structure by predicting sites of metabolism or characterizing formation of metabolite-biomolecule adducts. However, the majority of reactive metabolites are formed by multiple metabolic steps, and understanding the progenitor molecule's network-level behavior necessitates an integrative approach that blends multiple site of metabolism and structure inference models. Our previously developed tool, XenoNet 1.0, generates metabolic networks, where nodes are molecules and weighted edges are metabolic transformations. We extend XenoNet with a bidirectional message passing neural network that integrates edge feature information and local network structure using edge-conditioned graph convolutions and jumping knowledge to predict the authenticity of inferred Phase I metabolite structures. Our model significantly outperformed prior work and algorithmic baselines on a data set of 311 networks and 6606 intermediates annotated using a chemically diverse set of 20 736 individual in vitro and in vivo reaction records accounting for 92.3% of all human Phase I metabolism in the Accelrys Metabolite Database. Cross-validated predictions resulted in area under the receiver operating characteristic curves of 88.5% and 87.6% for separating experimentally observed and unobserved metabolites at global and network levels, respectively. Further analysis verified robustness to networks of varying depth and breadth, accurate detection of metabolites, such as d,l-methamphetamine, that are experimentally observed or unobserved in different network contexts, extraction of important metabolic subnetworks, and identification of known bioactivation pathways, such as for nimesulide and terbinafine. By exploiting network structures, our approach accurately suggests unreported metabolites for experimental study and may rationalize modifications for avoiding deleterious pathways antecedent to reactive metabolite formation.
Topics: Humans; Neural Networks, Computer; Molecular Structure; Metabolic Networks and Pathways; Terbinafine
PubMed: 36926871
DOI: 10.1021/acs.jcim.2c01383 -
ACS Chemical Biology Oct 2022Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a cancer predisposition syndrome driven by mutation of the tumor suppressor fumarate hydratase (FH)....
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a cancer predisposition syndrome driven by mutation of the tumor suppressor fumarate hydratase (FH). Inactivation of FH causes accumulation of the electrophilic oncometabolite fumarate. In the absence of methods for reactivation, tumor suppressors can be targeted via identification of synthetic lethal interactions using genetic screens. Inspired by recent advances in chemoproteomic target identification, here, we test the hypothesis that the electrophilicity of the HLRCC metabolome may produce unique susceptibilities to covalent small molecules, a phenomenon we term conditional covalent lethality. Screening a panel of chemically diverse electrophiles, we identified a covalent ligand, MP-1, that exhibits FH-dependent cytotoxicity. Synthesis and structure-activity profiling identified key molecular determinants underlying the molecule's effects. Chemoproteomic profiling of cysteine reactivity together with clickable probes validated the ability of MP-1 to engage an array of functional cysteines, including one lying in the Zn-finger domain of the tRNA methyltransferase enzyme TRMT1. TRMT1 overexpression rescues tRNA methylation from inhibition by MP-1 and partially attenuates the covalent ligand's cytotoxicity. Our studies highlight the potential for covalent metabolites and small molecules to synergistically produce novel synthetic lethal interactions and raise the possibility of applying phenotypic screening with chemoproteomic target identification to identify new functional oncometabolite targets.
Topics: Humans; Fumarate Hydratase; Cysteine; Ligands; Neoplastic Syndromes, Hereditary; Fumarates; tRNA Methyltransferases; RNA, Transfer
PubMed: 36190452
DOI: 10.1021/acschembio.2c00384 -
Biology of Reproduction Aug 2021Recent evidence indicates that niclosamide is an anti-cancer compound that is able to inhibit several signaling pathways. Although niclosamide has previously been...
Recent evidence indicates that niclosamide is an anti-cancer compound that is able to inhibit several signaling pathways. Although niclosamide has previously been identified by high-throughput screening platforms as a potential effective compound against several cancer types, no direct binding interactions with distinct biological molecule(s) has been established. The present study identifies key signal transduction mechanisms altered by niclosamide in ovarian cancer. Using affinity purification with a biotin-modified niclosamide derivative and mass spectrometry analysis, several RNA-binding proteins (RBPs) were identified. We chose the two RBPs, FXR1 and IGF2BP2, for further analysis. A significant correlation exists in which high-expression of FXR1 or IGF2BP2 is associated with reduced survival of ovarian cancer patients. Knockdown of FXR1 or IGF2BP2 in ovarian cancer cells resulted in significantly reduced cell viability, adhesion, and migration. Furthermore, FXR1 or IGF2BP2 deficient ovarian cancer cells exhibited reduced response to most doses of niclosamide showing greater cell viability than those with intact RBPs. These results suggest that FXR1 and IGF2BP2 are direct targets of niclosamide and could have critical activities that drive multiple oncogenic pathways in ovarian cancer.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Humans; Mice; Niclosamide; Ovarian Neoplasms; RNA-Binding Proteins
PubMed: 33855343
DOI: 10.1093/biolre/ioab071 -
Molecules (Basel, Switzerland) Jan 2023Understanding the inherent timescales of large bubbles in DNA is critical to a thorough comprehension of its physicochemical characteristics, as well as their potential...
Understanding the inherent timescales of large bubbles in DNA is critical to a thorough comprehension of its physicochemical characteristics, as well as their potential role on helix opening and biological function. In this work, we employ the coarse-grained Peyrard-Bishop-Dauxois model of DNA to study relaxation dynamics of large bubbles in homopolymer DNA, using simulations up to the microsecond time scale. By studying energy autocorrelation functions of relatively large bubbles inserted into thermalised DNA molecules, we extract characteristic relaxation times from the equilibration process for both adenine-thymine (AT) and guanine-cytosine (GC) homopolymers. Bubbles of different amplitudes and widths are investigated through extensive statistics and appropriate fittings of their relaxation. Characteristic relaxation times increase with bubble amplitude and width. We show that, within the model, relaxation times are two orders of magnitude longer in GC sequences than in AT sequences. Overall, our results confirm that large bubbles leave a lasting impact on the molecule's dynamics, for times between 0.5-500 ns depending on the homopolymer type and bubble shape, thus clearly affecting long-time evolutions of the molecule.
Topics: Computer Simulation; Base Sequence; Models, Chemical; Models, Molecular; DNA; Cytosine; Guanine; Adenine; Thymine
PubMed: 36770707
DOI: 10.3390/molecules28031041 -
Frontiers in Chemistry 2024Metal ions can perform multiple roles ranging from regulatory to structural and are crucial for cell function. While some metal ions like Na are ubiquitously present at... (Review)
Review
Metal ions can perform multiple roles ranging from regulatory to structural and are crucial for cell function. While some metal ions like Na are ubiquitously present at high concentrations, other ions, especially Ca and transition metals, such as Zn or Cu are regulated. The concentrations above or below the physiological range cause severe changes in the behavior of biomolecules that bind them and subsequently affect the cell wellbeing. This has led to the development of specialized protocols to study metal ion binding biomolecules in bulk conditions that mimic the cell environment. Recently, there is growing evidence of influence of post-transcriptional and post-translational modifications on the affinity of the metal ion binding sites. However, such targets are difficult to obtain in amounts required for classical biophysical experiments. Single molecule techniques have revolutionized the field of biophysics, molecular and structural biology. Their biggest advantage is the ability to observe each molecule's interaction independently, without the need for synchronization. An additional benefit is its extremely low sample consumption. This feature allows characterization of designer biomolecules or targets obtained coming from natural sources. All types of biomolecules, including proteins, DNA and RNA were characterized using single molecule methods. However, one group is underrepresented in those studies. These are the metal ion binding biomolecules. Single molecule experiments often require separate optimization, due to extremely different concentrations used during the experiments. In this review we focus on single molecule methods, such as single molecule FRET, nanopores and optical tweezers that are used to study metal ion binding biomolecules. We summarize various examples of recently characterized targets and reported experimental conditions. Finally, we discuss the potential promises and pitfalls of single molecule characterization on metal ion binding biomolecules.
PubMed: 38680456
DOI: 10.3389/fchem.2024.1378447 -
Nature Communications Aug 2023In molecular tunnel junctions, where the molecule is decoupled from the electrodes by few-monolayers-thin insulating layers, resonant charge transport takes place by...
In molecular tunnel junctions, where the molecule is decoupled from the electrodes by few-monolayers-thin insulating layers, resonant charge transport takes place by sequential charge transfer to and from the molecule which implies transient charging of the molecule. The corresponding charge state transitions, which involve tunneling through the insulating decoupling layers, are crucial for understanding electrically driven processes such as electroluminescence or photocurrent generation in such a geometry. Here, we use scanning tunneling microscopy to investigate the decharging of single ZnPc and HPc molecules through NaCl films of 3 to 5 monolayers thickness on Cu(111) and Au(111). To this end, we approach the tip to the molecule at resonant tunnel conditions up to a regime where charge transport is limited by tunneling through the NaCl film. The resulting saturation of the tunnel current is a direct measure of the lifetimes of the anionic and cationic states, i.e., the molecule's charge-state lifetime, and thus provides a means to study charge dynamics and, thereby, exciton dynamics. Comparison of anion and cation lifetimes on different substrates reveals the critical role of the level alignment with the insulator's conduction and valence band, and the metal-insulator interface state.
PubMed: 37591847
DOI: 10.1038/s41467-023-40692-1 -
Journal of Orthopaedic Research :... Apr 2021Vitamin C (ascorbic acid), is an important antioxidant that has been applied broadly in the field of orthopaedics. Current research on vitamin C examines the molecule's... (Review)
Review
Vitamin C (ascorbic acid), is an important antioxidant that has been applied broadly in the field of orthopaedics. Current research on vitamin C examines the molecule's role in bone and tendon physiology, as well as joint replacement and Postoperative pain. Most laboratory and human studies associate the use of vitamin C with improved bone health and tendon healing. Recent literature moderately supports the use of vitamin C to improve functional outcomes, decreased postoperative pain, and prevent complex regional pain syndrome following orthopaedic procedures. The perioperative use of vitamin C in patients undergoing joint replacement surgery and anterior cruciate ligament reconstruction is still under investigation. Overall, there is need for high-quality human trials to confirm whether vitamin C can potentiate the outcomes of orthopaedic procedures and to determine optimal dosage and means of administration to maximize its proposed benefits. The purpose of this review was to summarize the application of vitamin C in orthopaedic practices and to identify potential areas for future study.
Topics: Animals; Anterior Cruciate Ligament; Anterior Cruciate Ligament Injuries; Anterior Cruciate Ligament Reconstruction; Antioxidants; Arthroplasty, Replacement; Ascorbic Acid; Bone and Bones; Clinical Trials as Topic; Humans; Orthopedics; Osteoporosis; Pain, Postoperative; Perioperative Period; Randomized Controlled Trials as Topic; Tendons; Treatment Outcome
PubMed: 33300201
DOI: 10.1002/jor.24947 -
Wiley Interdisciplinary Reviews.... 2015The electronic configuration of the molecule is the foundation of its structure and reactivity. The spin state is one of the key characteristics arising from the... (Review)
Review
The electronic configuration of the molecule is the foundation of its structure and reactivity. The spin state is one of the key characteristics arising from the ordering of electrons within the molecule's set of orbitals. Organic molecules that have open-shell ground states and interesting physicochemical properties, particularly those influencing their spin alignment, are of immense interest within the up-and-coming field of molecular electronics. In this advanced review, we scrutinize various qualitative rules of orbital occupation and spin alignment, viz., the aufbau principle, Hund's multiplicity rule, and dynamic spin polarization concept, through the prism of quantum mechanics. While such rules hold in selected simple cases, in general the spin state of a system depends on a combination of electronic factors that include Coulomb and Pauli repulsion, nuclear attraction, kinetic energy, orbital relaxation, and static correlation. A number of fascinating chemical systems with spin states that fluctuate between triplet and open-shell singlet, and are responsive to irradiation, pH, and other external stimuli, are highlighted. In addition, we outline a range of organic molecules with intriguing non-aufbau orbital configurations. In such quasi-closed-shell systems, the singly occupied molecular orbital (SOMO) is energetically lower than one or more doubly occupied orbitals. As a result, the SOMO is not affected by electron attachment to or removal from the molecule, and the products of such redox processes are polyradicals. These peculiar species possess attractive conductive and magnetic properties, and a number of them that have already been developed into molecular electronics applications are highlighted in this review. 2015, 5:440-459. doi: 10.1002/wcms.1233 For further resources related to this article, please visit the WIREs website.
PubMed: 27774112
DOI: 10.1002/wcms.1233 -
International Journal of Molecular... Aug 2021The increasing number and complexity of structures containing RNA chains in the Protein Data Bank (PDB) have led to the need for automated structure annotation methods... (Review)
Review
The increasing number and complexity of structures containing RNA chains in the Protein Data Bank (PDB) have led to the need for automated structure annotation methods to replace or complement expert visual curation. This is especially true when searching for tertiary base motifs and substructures. Such base arrangements and motifs have diverse roles that range from contributions to structural stability to more direct involvement in the molecule's functions, such as the sites for ligand binding and catalytic activity. We review the utility of computational approaches in annotating RNA tertiary base motifs in a dataset of PDB structures, particularly the use of graph theoretical algorithms that can search for such base motifs and annotate them or find and annotate clusters of hydrogen-bond-connected bases. We also demonstrate how such graph theoretical algorithms can be integrated into a workflow that allows for functional analysis and comparisons of base arrangements and sub-structures, such as those involved in ligand binding. The capacity to carry out such automatic curations has led to the discovery of novel motifs and can give new context to known motifs as well as enable the rapid compilation of RNA 3D motifs into a database.
Topics: Algorithms; Databases, Nucleic Acid; Molecular Sequence Annotation; Nucleotide Motifs; RNA; Software; Workflow
PubMed: 34445259
DOI: 10.3390/ijms22168553 -
Frontiers in Pharmacology 2022Transthyretin (TTR) is a homotetrameric protein found in human serum and is implicated in fatal inherited amyloidoses. Destabilization of native TTR confirmation...
Transthyretin (TTR) is a homotetrameric protein found in human serum and is implicated in fatal inherited amyloidoses. Destabilization of native TTR confirmation resulting from mutation, environmental changes, and aging causes polymerization and amyloid fibril formation. Although several small molecules have been reported to stabilize the native state and inhibit TTR aggregation, prolonged use can cause serious side effects. Therefore, pharmacologically enhancing the degradation of TTR aggregates and kinetically stabilizing the native tetrameric structure with bioactive molecule(s) could be a viable therapeutic strategy to hinder the advancement of TTR amyloidoses. In this context, here we demonstrated α- and β-santalol, natural sesquiterpenes from sandalwood, as a potent TTR aggregation inhibitor and native state stabilizer using combined , , and experiments. We found that α- and β-santalol synergize to reduce wild-type (WT) and Val30Met (V30M) mutant TTR aggregates in novel strains expressing TTR fragments fused with a green fluorescent protein in body wall muscle cells. α- and β-Santalol extend the lifespan and healthspan of strains carrying TTR::EGFP and TTR::EGFP transgene by activating the SKN-1/Nrf2, autophagy, and proteasome. Moreover, α- and β-santalol directly interacted with TTR and reduced the flexibility of the thyroxine-binding cavity and homotetramer interface, which in turn increases stability and prevents the dissociation of the TTR tetramer. These data indicate that α- and β-santalol are the strong natural therapeutic intervention against TTR-associated amyloid diseases.
PubMed: 35784752
DOI: 10.3389/fphar.2022.924862