Interaction Of Small Molecules Research Articles

Discovery of potent small-molecule inhibitors of lipoprotein(a) formation

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a) (refs. 3–7). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) KIV7–8. We identify compounds that bind to apo(a) KIV7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a).

A Gastroenterologist's guide to drug interactions of small molecules for inflammatory bowel disease.

Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of four novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, and Ozanimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.

Abstract 4490: Targeting NQO1 with Episesaminol: A new therapeutic option identified for colorectal cancer using integrated systems biology and structural biology-based approach

Abstract Introduction: Colon and/or rectal cancer together constitute colorectal cancer (CRC), the 2nd most lethal and the 3rd common cancer worldwide. Drug resistance to modern chemotherapies results in decreased therapeutic efficacy and CRC treatment failure. Herein, multi-layered strategies are used for a better identification of the newer therapeutics. Methodology: Different publicly available datasets were used for the identification of the differentially expressed genes (DEGs) between normal and CRC tissues. miRNAs, lncRNAs and small molecules interacting with those DEGs were mined from various databases. A complex network of interacting mRNA-miRNAs-lncRNAs-small molecules was created using the Cytoscape. Hub RNAs, significant modules and cliques were identified using Cytohubba and MClique plugins. The mRNAs from the top 30 cliques were analyzed by expression, oncoprint, survival and gene ontology. Polyphenols from the PhenolExplorer database were also assessed for their druggability and toxicity properties to finally obtain druggable polyphenols (DPs). A two-step molecular docking was done using PyRx for mRNAs from top 30 cliques and DPs and the top ten complexes were docked again using AutoDock. Molecular dynamics simulation (MDS) is performed for the best fit protein-proposed DP vs protein-known drug using GROMACS. Results: 1915 DEGs, 2609 miRNAs, 1411 lncRNAs and 8790 small molecules (other than selected DPs) interactions were considered for generating a comprehensive interaction network. The 27 mRNAs from the top 30 cliques were subjected to an array of analyses. NCAPD2, CDK4 and FASN were found to be involved in different stages of CRC. IRF2BPL, CMPK1, CCNF and UST were found as survival biomarkers, whereas FAT4 was found to be the only genetically altered mRNA. Functional enrichment supported the analysis revealing significant CRC-associated gene ontology as well as pathways. 56 DPs when docked with the DEGs, the two-step docking revealed NQO1-Episesaminol to be the best target-drug complex. Results of docking were comparable when MDS was performed for NOQ1•Episesaminol Vs NQO1•Doxorubicin (approved drug). Conclusion: In the current interaction network and MDS-based integrated analysis, significant druggable CRC biomarkers and their newer therapeutic solutions were identified. MDS reveals NQO1•Episesaminol as a potential target•drug combination for CRC. Citation Format: Sohini Chakraborty, Gaurav Sharma, Sricheta Karmakar, Prarthana Chatterjee, Saptarshi Sinha, Pradipta Ghosh, Satarupa Banerjee. Targeting NQO1 with Episesaminol: A new therapeutic option identified for colorectal cancer using integrated systems biology and structural biology-based approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4490.

Soil metabolomics - current challenges and future perspectives

Soil is an extremely complex and dynamic matrix, in part, due to the wide diversity of organisms living within it. Soil organic matter (SOM) is the fundamental substrate on which the delivery of ecosystem services depends, providing the metabolic fuel to drive soil function. As such, studying the soil metabolome (the diversity and concentration of low molecular weight metabolites), as a subset of SOM, holds the potential to greatly expand our understanding of the behaviour, fate, interaction and functional significance of small organic molecules in soil. Encompassing a wide range of chemical classes (including amino acids, peptides, lipids and carbohydrates) and a large number of individual molecules (ca. n = 105 to 106), the metabolome is a resultant (indirect) output of several layers of a biological hierarchy, namely the metagenome, metatranscriptome and metaproteome. As such, it may also provide support and validation for these “multi-omics” datasets. We present a case for the increased use of untargeted metabolomics in soil biochemistry, particularly for furthering our fundamental understanding of the functions driving SOM composition and biogeochemical cycling. Further, we discuss the scale of the challenge in terms of metabolite extraction, analysis and interpretation in complex plant-soil-microbial systems. Lastly, we highlight key knowledge gaps which currently limit our use of metabolomic approaches to better understand soil processes, including: (i) interpretation of large untargeted metabolomic datasets; (ii) the source, emission and fate of soil-derived volatile organic compounds (VOCs), (iii) assessing temporal fluxes of metabolites, and (iv) monitoring ecological interactions in the rhizosphere. While the application of metabolomics in ecosystem science is still in its relative infancy, its importance in understanding the biochemical system in relation to regulation, management and underpinning the delivery of ecosystem services is key to further elucidating the complex links between organisms, as well as the fundamental ability of the biological community to process and cycle key nutrients.

Search for molecular descriptors and computer prediction of biological activity in a series of S-derivatives (1,2,4-triazole-3(2H)-yl)methyl)thiopyrimidines

Most pharmaceutical compounds interact with various molecular compositions in the body, leading to complex biological effects. Furthermore, during biotransformation, they may generate one or more metabolites with potent bioactive properties. Therefore, the development and careful use of new medications require thorough examination of their biological impact profiles, including considerations of human metabolic processes. In silico techniques are currently widely used to evaluate the interactions of emerging drug candidates with pharmacological conditions and predict their metabolic conversions. To investigate the bioactivity of compounds based on the structure of 1,2,4-triazole-3(2H)-thione with pyrimidine-2-thiol, we generated a combinatorial library of bioregulators using the computer programs SuperPred and SwissADME. The relevance of this research is underscored by the ongoing quest for novel biomolecular compounds that are highly effective yet low in toxicity, spanning both natural and synthetic sources. Much attention is directed towards nitrogen-containing heterocycles, particularly derivatives of 1,2,4-triazole, due to their substantial medical and biological potential. The aim of the work is to create a combinatorial library of bioregulators, which contains the structures of 1,2,4-triazole and pyrimidine, and to carry out in silico screening of heterocycle derivatives using the SuperPred web server to determine promising directions for the study of their bioactivity. Materials and methods. The subject of our research is S-derivatives of (1,2,4-triazole-3(2H)-yl)methyl)thiopyrimidines. Virtual screening of compounds was carried out using the SuperPred computer program. The ADME study was performed using the free service SwissADME, which is used to evaluate the pharmacokinetics, bioavailability, and interaction of small molecules with enzymes in medicinal chemistry. Results. Predicting the likelihood of a substance demonstrating a particular biological activity enables the selection of the most appropriate tests for studying the activity of a given chemical compound, as well as identifying which substances available to the researcher are most likely to enhance the effectiveness of the effects. This principle is grounded in the concept that “the biological activity of a substance is a function of its chemical structure”. Such predictions are generated based on the structural formula of a chemical compound and can be made during the planning stage of synthesis. Conclusions. A combinatorial library of bioregulators was created by combining the structure of 1,2,4-triazole-3(2H)-thione with pyrimidine-2-thiol. The conducted virtual screening of the 1,2,4-triazole-3(2H)-thione heterocycle with pyrimidine-2-thiol shows promise for obtaining non-toxic compounds with antineoplastic biological activity. Screening of derivatives, particularly S-derivatives of (1,2,4-triazole-3(2H)-yl)methyl)thiopyrimidines, indicates the potential for discovering biologically active substances with antineoplastic, antibacterial, analgesic, antidiabetic, antihypertensive, and other types of biological activities within this compound series.

Catalyst-free late-stage functionalization to assemble α-acyloxyenamide electrophiles for selectively profiling conserved lysine residues

Covalent probes coupled with chemical proteomics represent a powerful method for investigating small molecule and protein interactions. However, the creation of a reactive warhead within various ligands to form covalent probes has been a major obstacle. Herein, we report a convenient and robust process to assemble a unique electrophile, an α-acyloxyenamide, through a one-step late-stage coupling reaction. This procedure demonstrates remarkable tolerance towards other functional groups and facilitates ligand-directed labeling in proteins of interest. The reactive group has been successfully incorporated into a clinical drug targeting the EGFR L858R mutant, erlotinib, and a pan-kinase inhibitor. The resulting probes have been shown to be able to covalently engage a lysine residue proximal to the ATP-binding pocket of the EGFR L858R mutant. A series of active sites, and Mg2+, ATP-binding sites of kinases, such as K33 of CDK1, CDK2, CDK5 were detected. This is the first report of engaging these conserved catalytic lysine residues in kinases with covalent inhibition. Further application of this methodology to natural products has demonstrated its success in profiling ligandable conserved lysine residues in whole proteome. These findings offer insights for the development of new targeted covalent inhibitors (TCIs).

Identification of hub genes significantly linked to temporal lobe epilepsy and apoptosis via bioinformatics analysis.

Epilepsy stands as an intricate disorder of the central nervous system, subject to the influence of diverse risk factors and a significant genetic predisposition. Within the pathogenesis of temporal lobe epilepsy (TLE), the apoptosis of neurons and glial cells in the brain assumes pivotal importance. The identification of differentially expressed apoptosis-related genes (DEARGs) emerges as a critical imperative, providing essential guidance for informed treatment decisions. We obtained datasets related to epilepsy, specifically GSE168375 and GSE186334. Utilizing differential expression analysis, we identified a set of 249 genes exhibiting significant variations. Subsequently, through an intersection with apoptosis-related genes, we pinpointed 16 genes designated as differentially expressed apoptosis-related genes (DEARGs). These DEARGs underwent a comprehensive array of analyses, including enrichment analyses, biomarker selection, disease classification modeling, immune infiltration analysis, prediction of miRNA and transcription factors, and molecular docking analysis. In the epilepsy datasets examined, we successfully identified 16 differentially expressed apoptosis-related genes (DEARGs). Subsequent validation in the external dataset GSE140393 revealed the diagnostic potential of five biomarkers (CD38, FAIM2, IL1B, PAWR, S100A8) with remarkable accuracy, exhibiting an impressive area under curve (AUC) (The overall AUC of the model constructed by the five key genes was 0.916, and the validation set was 0.722). Furthermore, a statistically significant variance (p < 0.05) was observed in T cell CD4 naive and eosinophil cells across different diagnostic groups. Exploring interaction networks uncovered intricate connections, including gene-miRNA interactions (164 interactions involving 148 miRNAs), gene-transcription factor (TF) interactions (22 interactions with 20 TFs), and gene-drug small molecule interactions (15 interactions involving 15 drugs). Notably, IL1B and S100A8 demonstrated interactions with specific drugs. In the realm of TLE, we have successfully pinpointed noteworthy differentially expressed apoptosis-related genes (DEARGs), including CD38, FAIM2, IL1B, PAWR, and S100A8. A comprehensive understanding of the implications associated with these identified genes not only opens avenues for advancing our comprehension of the underlying pathophysiology but also bears considerable potential in guiding the development of innovative diagnostic methodologies and therapeutic interventions for the effective management of epilepsy in the future.

Q-BioLiP: A Comprehensive Resource for Quaternary Structure-based Protein–ligand Interactions

Abstract Since its establishment in 2013, BioLiP has become one of the widely used resources for protein–ligand interactions. Nevertheless, several known issues occurred with it over the past decade. For example, the protein–ligand interactions are represented in the form of single-chain-based tertiary structures, which may be inappropriate as many interactions involve multiple protein chains (known as quaternary structures). We sought to address these issues, resulting in Q-BioLiP, a comprehensive resource for quaternary structure-based protein–ligand interactions. The major features of Q-BioLiP include: (1) representing protein structures in the form of quaternary structures rather than single-chain-based tertiary structures; (2) pairing DNA/RNA chains properly rather than separation; (3) providing both experimental and predicted binding affinities; (4) retaining both biologically relevant and irrelevant interactions to alleviate the problem of the wrong justification of ligands’ biological relevance; and (5) developing a new quaternary structure-based algorithm for the modelling of protein–ligand complex structure. With these new features, Q-BioLiP is expected to be a valuable resource for studying biomolecule interactions, including protein–small molecule interaction, protein–metal ion interaction, protein–peptide interaction, protein–protein interaction, protein–DNA/RNA interaction, and RNA–small molecule interaction. Q-BioLiP is freely available at https://yanglab.qd.sdu.edu.cn/Q-BioLiP/.

Speeding-up the Determination of Protein-Ligand Affinities by STD NMR: The Reduced Data Set STD NMR Approach (rd-STD NMR).

STD NMR spectroscopy is a powerful ligand-observed NMR tool for screening and characterizing the interactions of small molecules and low molecular weight fragments with a given macromolecule, identifying the main intermolecular contacts in the bound state. It is also a powerful analytical technique for the accurate determination of protein-ligand dissociation constants (KD) of medium-to-weak affinity, of interest in the pharmaceutical industry. However, accurate KD determination and epitope mapping requires a long series of experiments at increasing saturation times to carry out a full analysis using the so-called STD NMR build-up curve approach and apply the "initial slopes approximation". Here, we have developed a new protocol to bypass this important limitation, which allows us to obtain initial slopes by using just two saturation times and, hence, to very quickly determine precise protein-ligand dissociation constants by STD NMR.

Enhanced mapping of small-molecule binding sites in cells.

Photoaffinity probes are routinely utilized to identify proteins that interact with small molecules. However, despite this common usage, resolving the specific sites of these interactions remains a challenge. Here we developed a chemoproteomic workflow to determine precise protein binding sites of photoaffinity probes in cells. Deconvolution of features unique to probe-modified peptides, such as their tendency to produce chimeric spectra, facilitated the development of predictive models to confidently determine labeled sites. This yielded an expansive map of small-molecule binding sites on endogenous proteins and enabled the integration with multiplexed quantitation, increasing the throughput and dimensionality of experiments. Finally, using structural information, we characterized diverse binding sites across the proteome, providing direct evidence of their tractability to small molecules. Together, our findings reveal new knowledge for the analysis of photoaffinity probes and provide a robust method for high-resolution mapping of reversible small-molecule interactions en masse in native systems.

Illustrated Procedure to Perform Molecular Docking Using PyRx and Biovia Discovery Studio Visualizer: A Case Study of 10kt With Atropine

Molecular docking is a bioinformatic modeling technique used in structure-based drug design. It has been a vital tool in drug discovery and the study of biological systems. It plays a crucial role in predicting the interactions of small molecules (ligands) with the binding site of a protein of interest. This helps in designing more effective and specific drugs. This tutorial aimed at demonstrating a step-by-step procedure for the combined usage of PyRx and Biovia Discovery Studio visualizer in molecular docking.

Quantification of Binding of Small Molecules to Native Proteins Overexpressed in Living Cells.

The affinity and selectivity of small molecules for proteins drive drug discovery and development. We report a fluorescent probe cellular binding assay (FPCBA) for determination of these values for native (untagged) proteins overexpressed in living cells. This method uses fluorophores such as Pacific Blue (PB) linked to cell-permeable protein ligands to generate probes that rapidly and reversibly equilibrate with intracellular targets, as established by kinetic assays of cellular uptake and efflux. To analyze binding to untagged proteins, an internal ribosomal entry site (IRES) vector was employed that allows a single mRNA to encode both the protein target and a separate orthogonal fluorescent protein (mVenus). This enabled cellular uptake of the probe to be correlated with protein expression by flow cytometry, allowing measurement of cellular dissociation constants (Kd) of the probe. This approach was validated by studies of the binding of allosteric activators to eight different Protein Kinase C (PKC) isozymes. Full-length PKCs expressed in transiently transfected HEK293T cells were used to measure cellular Kd values of a probe comprising PB linked to the natural product phorbol via a carbamate. These values were further used to determine competitive binding constants (cellular Ki values) of the nonfluorescent phorbol ester PDBu and the anticancer agent bryostatin 1 for each isozyme. For some PKC-small molecule pairs, these cellular Ki values matched known biochemical Ki values, but for others, altered selectivity was observed in cells. This approach can facilitate quantification of interactions of small molecules with physiologically relevant native proteins.

Molecular dynamics study on micelle-small molecule interactions: developing a strategy for an extensive comparison

Theoretical predictions of the solubilizing capacity of micelles and vesicles present in intestinal fluid are important for the development of new delivery techniques and bioavailability improvement. A balance between accuracy and computational cost is a key factor for an extensive study of numerous compounds in diverse environments. In this study, we aimed to determine an optimal molecular dynamics (MD) protocol to evaluate small-molecule interactions with micelles composed of bile salts and phospholipids. MD simulations were used to produce free energy profiles for three drug molecules (danazol, probucol, and prednisolone) and one surfactant molecule (sodium caprate) as a function of the distance from the colloid center of mass. To address the challenges associated with such tasks, we compared different simulation setups, including freely assembled colloids versus pre-organized spherical micelles, full free energy profiles versus only a few points of interest, and a coarse-grained model versus an all-atom model. Our findings demonstrate that combining these techniques is advantageous for achieving optimal performance and accuracy when evaluating the solubilization capacity of micelles.Graphical abstractAll-atom (AA) and coarse-grained (CG) umbrella sampling (US) simulations and point-wise free energy (FE) calculations were compared to their efficiency to computationally analyze the solubilization of active pharmaceutical ingredients in intestinal fluid colloids.

In silico identification and characterization of small molecule binding to the CD1d immunoreceptor

CD1 immunoreceptors are a non-classical major histocompatibility complex (MHC) that present antigens to T cells to elucidate immune responses against disease. The antigen repertoire of CD1 has been composed primarily of lipids until recently when CD1d-restricted T cells were shown to be activated by non-lipidic small molecules, such as phenyl pentamethyl dihydrobenzofuran sulfonate (PPBF) and related benzofuran sulfonates. To date structural insights into PPBF/CD1d interactions are lacking, so it is unknown whether small molecule and lipid antigens are presented and recognized through similar mechanisms. Furthermore, it is unknown whether CD1d can bind to and present a broader range of small molecule metabolites to T cells, acting out functions analogous to the MHC class I related protein MR1. Here, we perform in silico docking and molecular dynamics simulations to structurally characterize small molecule interactions with CD1d. PPBF was supported to be presented to T cell receptors through the CD1d F’ pocket. Virtual screening of CD1d against more than 17,000 small molecules with diverse geometry and chemistry identified several novel scaffolds, including phytosterols, cholesterols, triterpenes, and carbazole alkaloids, that serve as candidate CD1d antigens. Protein-ligand interaction profiling revealed conserved residues in the CD1d F’ pocket that similarly anchor small molecules and lipids. Our results suggest that CD1d could have the intrinsic ability to bind and present a broad range of small molecule metabolites to T cells to carry out its function beyond lipid antigen presentation. Communicated by Ramaswamy H. Sarma

Synthesis, structure elucidation, SC-XRD/DFT, molecular modelling simulations and DNA binding studies of 3,5-diphenyl-4,5-dihydro-1H-pyrazole chalcones

Deoxyribonucleic acid (DNA) acts as the most important intracellular target for various drugs. Exploring the DNA binding interactions of small bioactive molecules offers a structural guideline for designing new drugs with higher clinical efficacy and enhanced selectivity. This study presents the facile synthesis of pyrazoline-derived compounds (4a)-(4f) by reacting substituted chalcones with hydrazine hydrate using formic acid. The structure elucidation of substituted pyrazoline compounds was carried out using 1H-NMR, FT-IR and elemental analyses. While the crystal structures of two compounds (4a) and (4b) have been resolved by single-crystal X-ray diffraction (SC-XRD) analysis. Hirshfeld surface analysis also endorsed their greater molecular stability. Computational calculations at DFT/B3LYP/6-311++G(d,p) were executed to compare the structural properties (bond angle and bond length) and explore reactivity descriptors, frontier molecular orbitals (FMO), Mulliken atomic charges (MAC), molecular electrostatic potential (MEP) and electronic properties. All the compounds were evaluated for DNA binding interactions by UV-Vis spectrophotometric analysis. The results revealed that compounds (4a)-(4f) bind to DNA via non-covalent binding mode having binding constant values ranging from 1.22 × 103 to 6.81 × 104 M−1. The negative values of Gibbs free energy also proved the interaction of studied compounds with DNA as a spontaneous process. The findings of molecular docking simulations depicted that these studied compounds showed significant binding interactions with DNA and these results were consistent with experimental findings. Compound (4b) was concluded as the most potent compound of the series with the highest binding constant (4.95 × 104) and strongest binding affinity (-8.48 kcal/mol). Communicated by Ramaswamy H. Sarma

Kinetic FRET Assay to Measure Binding-Induced Conformational Changes of Nucleic Acids.

The interaction of small molecules or proteins with RNA or DNA often involves changes in the nucleic acid (NA) folding and structure. A biophysical characterization of these processes helps us to understand the underlying molecular mechanisms. Here, we propose kinFRET (kinetics Förster resonance energy transfer), a real-time ensemble FRET methodology to measure binding and folding kinetics. With kinFRET, the kinetics of conformational changes of NAs (DNA or RNA) upon analyte binding can be directly followed via a FRET signal using a chip-based biosensor. We demonstrate the utility of this approach with two representative examples. First, we monitored the conformational changes of different formats of an aptamer (MN19) upon interaction with small-molecule analytes. Second, we characterized the binding kinetics of RNA recognition by tandem K homology (KH) domains of the human insulin-like growth factor II mRNA-binding protein 3 (IMP3), which reveals distinct kinetic contributions of the two KH domains. Our data demonstrate that kinFRET is well suited to study the kinetics and conformational changes of NA-analyte interactions.

SwissParam 2023: A Modern Web-Based Tool for Efficient Small Molecule Parametrization.

Most steps of drug discovery are now routinely supported and accelerated by computer-aided drug design tools. Among them, structure-based approaches use the three-dimensional structure of the targeted biomacromolecule as a major source of information. When it comes to calculating the interactions of small molecules with proteins using the equations of molecular mechanics, topologies, atom typing, and force field parameters are required. However, generating parameters for small molecules remains challenging due to the large number of existing chemical groups. The SwissParam web tool was first released in 2011 with the aim of generating parameters and topologies for small molecules based on the Merck molecular force field (MMFF) while being compatible with the CHARMM22/27 force field. Here, we present an updated version of SwissParam, providing various new features, including the possibility to setup covalent ligands. Molecules can now be imported from different file formats or via a molecular sketcher. The MMFF-based approach has been updated to provide parameters and topologies compatible with the CHARMM36 force field. An option was added to generate small molecule parametrizations following the CHARMM General Force Field via the multipurpose atom-typer for CHARMM (MATCH) approach. Additionally, SwissParam now generates information on probable alternative tautomers and protonation states of the query molecule so that the user can consider all microspecies relevant to its compound. The new version of SwissParam is freely available at www.swissparam.ch and can also be accessed through a newly implemented command-line interface.

Insights into the mechanism of binding of doxorubicin and a chlorin compound with 22-mer c-Myc G quadruplex

BackgroundThe interaction of small molecules with G quadruplexes is in focus due to its role in molecular recognition and therapeutic drug design. Stabilization of G-quadruplex structures in the promoter regions of oncogenes by small molecule binding has been demonstrated as a potential approach for cancer therapy. MethodsIn this study, electronic spectroscopy (ultraviolet-visible, fluorescence, circular dichroism), differential scanning calorimetry, and molecular modeling were employed to explore the interactions between the chemotherapy drug doxorubicin and a chlorin compound 5,10,15,20-tetraphenyl-[2,3]-[bis(carboxy)-methano]chlorin (H2TPC(DAC)), and the c-Myc 22-mer G quadruplex DNA. ResultsSpectroscopic studies indicated external binding of the compounds with partial stacking at the end quartets. Calorimetric studies and temperature dependent circular dichroism data displayed increased melting temperatures of G quadruplex structure on binding with the compounds. Circular dichroism spectra indicated that the G quadruplex structure is intact upon ligand binding. Both the compounds showed binding affinities of the order of 106 M−1. Fluorescence lifetime studies revealed static quenching as major mechanism for fluorescence quenching. Polymerase chain reaction stop assay hinted that binding of both ligands under study could inhibit the amplification of the DNA sequence. ConclusionResults show that doxorubicin and H2TPC(DAC) bind to the 22-mer c-Myc quadruplex structure with good affinity and induce stability. SignificanceDoxorubicin and H2TPC(DAC) have demonstrated their affinity towards c-Myc G quadruplex DNA, stabilizing it and inhibiting expression and polymerization. The results can be of practical use in designing new analogs for the two compounds, which can become potent anti-cancer agents targeting the c-Myc GQ structure.

Adsorption Dynamics of Uremic Toxins to Novel Modified Magnetic Nanoparticles.

Kidney dysfunction leads to the retention of metabolites in the blood compartment, some of which reach toxic levels. Uremic toxins are associated with the progression of kidney disease and other symptoms of kidney failure (i.e., nausea, itchiness, and hypertension). Toxin removal ameliorates symptoms and reduces further organ damage, but membrane-based methods are inadequate for this purpose. Engineered adsorbents may facilitate enhanced removal of retained toxins, especially those bound strongly by proteins. Poly 2-(methacryloyloxy)ethyl phosphorylcholine-co-β-cyclodextrin (p(MPC-co-PMβCD)) coated magnetic nanoparticles are synthesized, characterized for their physicochemical properties (Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), thermogravimetric analysis(TGA), gel permeation chromatography(GPC), and transmission electron microscope (TEM), and evaluated toxin adsorption from a complex solution for the first time to quantify the effects of film chemistry and incubation time on the adsorbed toxinome (the collection of toxins). Uremic toxins are bound by even "low-fouling" polymer films themselves; providing further insight into how small molecule interactions with "low-fouling" films may affect protein-surface interactions. These results suggest a dynamic interaction between toxins and surfaces that is not driven by solution concentration alone. This knowledge will help advance the design of novel adsorbent films for clearing uremic toxins.

Design, synthesis, and structure-activity relationship of a bicyclic HBV capsid assembly modulator chemotype leading to the identification of clinical candidate AB-506

Disruption of the HBV capsid assembly process through small-molecule interaction with HBV core protein is a validated target for the suppression of hepatitis B viral replication and the development of new antivirals. Through combination of key structural features associated with two distinct series of capsid assembly modulators, a novel aminochroman-based chemotype was identified. Optimization of anti-HBV potency through generation of SAR in addition to further core modifications provided a series of related functionalized aminoindanes. Key compounds demonstrated excellent cellular potency in addition to favorable ADME and pharmacokinetic profiles and were shown to be highly efficacious in a mouse model of HBV replication. Aminoindane derivative AB-506 was subsequently advanced into clinical development.