Applications of machine learning in computer-aided drug discovery.

Machine learning (ML) has revolutionised the field of structure-based drug design (SBDD) in recent years. During the training stage, ML techniques typically analyse large amounts of experimentally determined data to create predictive models in order to inform the drug discovery process. Deep learning (DL) is a subfield of ML, that relies on multiple layers of a neural network to extract significantly more complex patterns from experimental data, and has recently become a popular choice in SBDD.

Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscles and Structure-Activity Relationship.

Despite large investments from academia and industry, heart failure, which results from a disruption of the contractile apparatus, remains a leading cause of death. Cardiac muscle contraction is a calcium-dependent mechanism, which is regulated by the troponin protein complex (cTn) and specifically by the N-terminal domain of its calcium-binding subunit (cNTnC). There is an increasing need for the development of small molecules that increase calcium sensitivity without altering the systolic calcium concentration, thereby strengthening the cardiac function.

Targeting Troponin C with Small Molecules Containing Diphenyl Moieties: Calcium Sensitivity Effects on Striated Muscle and Structure Activity Relationship.

Despite large investments from academia and industry, heart failure, which results from a disruption of the contractile apparatus, remains a leading cause of death. Cardiac muscle contraction is a calcium-dependent mechanism, which is regulated by the troponin protein complex (cTn) and specifically by the N-terminal domain of its calcium binding subunit (cNTnC). There is an increasing need for the development of small molecules that increase calcium sensitivity without altering systolic calcium concentration, thereby strengthening cardiac function.

Computational Exploration and Characterization of Potential Calcium Sensitizing Mutations in Cardiac Troponin C.

Calcium-dependent heart muscle contraction is regulated by the cardiac troponin protein complex (cTn) and specifically by the N-terminal domain of its calcium binding subunit (cNTnC). cNTnC contains one calcium binding site (site II), and altered calcium binding in this site has been studied for decades. It has been previously shown that cNTnC mutants, which increase calcium sensitization may have therapeutic benefits, such as restoring cardiac muscle contractility and functionality post-myocardial infarction events.

Actives-Based Receptor Selection Strongly Increases the Success Rate in Structure-Based Drug Design and Leads to Identification of 22 Potent Cancer Inhibitors.

Computer-aided drug design, an important component of the early stages of the drug discovery pipeline, routinely identifies large numbers of false positive hits that are subsequently confirmed to be experimentally inactive compounds. We have developed a methodology to improve true positive prediction rates in structure-based drug design and have successfully applied the protocol to twenty target systems and identified the top three performing conformers for each of the targets. Receptor performance was evaluated based on the area under the curve of the receiver operating characteristic curve for two independent sets of known actives.

The effect of Mg on Ca binding to cardiac troponin C in hypertrophic cardiomyopathy associated TNNC1 variants.

Cardiac troponin C (cTnC) is the critical Ca -sensing component of the troponin complex. Binding of Ca to cTnC triggers a cascade of conformational changes within the myofilament that culminate in force production. Hypertrophic cardiomyopathy (HCM)-associated TNNC1 variants generally induce a greater degree and duration of Ca binding, which may underly the hypertrophic phenotype.

Adaptative Steered Molecular Dynamics Study of Mutagenesis Effects on Calcium Affinity in the Regulatory Domain of Cardiac Troponin C.

Calcium-dependent cardiac muscle contraction is regulated by the protein complex troponin (cTn) and specifically by the regulatory N-terminal domain (N-cTnC) which contains one active Ca binding site (site II). It has been previously shown that cardiac muscle contractility and functionality is affected by mutations in N-cTnC which alter calcium binding affinity. Here, we describe the application of adaptive steered molecular dynamics to characterize the influence of N-cTnC mutations on site II calcium binding affinity.

Nuclear magnetic resonance-based serum metabolomic analysis reveals different disease evolution profiles between septic shock survivors and non-survivors.

Background: Septic shock is the most severe phase of sepsis and is associated with high rates of mortality. However, early stage prediction of septic shock outcomes remains difficult. Metabolomic techniques have emerged as a promising tool for improving prognosis.

Nuclear magnetic resonance metabolomics and human liver diseases: The principles and evidence associated with protein and carbohydrate metabolism.

During the last decade, metabolomics has become widely used in the field of human diseases. Numerous studies have demonstrated that this is a powerful technique for improving the understanding, diagnosis and management of various types of liver disease, such as acute and chronic liver diseases, and liver transplantation. Nuclear magnetic resonance (NMR) spectroscopy is one of the two most commonly applied methods for metabolomics.

Solution structure of a truncated anti-MUC1 DNA aptamer determined by mesoscale modeling and NMR.

Mucin 1 is a well-established target for the early diagnosis of epithelial cancers. The nucleotides of the S1.3/S2.

Deuteration of water enables self-organization of phospholipid-based reverse micelles.

Phospholipid-based reverse micelles are composed of branched cylinders. Their branching points are known to attract themselves and to slide along branches. The rate of this sliding is governed by the lifetime of H(D)-bonded water bridges between phospholipid molecules.

The DNA structure responds differently to physiological concentrations of K(+) or Na(+).

The influence of monovalent cations on DNA conformation and readout is an open question. This NMR study of DNA with either Na(+) or K(+) at physiological concentrations shows that the nature of the cation affects the (31)P chemical shifts (deltaP) and the sequential distances H2'(i)-H6/8(i+1), H2"(i)-H6/8(i+1), and H6/8(i)-H6/8(i+1). The deltaP and distance variations ascertain that the nature of the cation affects the DNA overall structure, i.

Solution structure of a purine rich hexaloop hairpin belonging to PGY/MDR1 mRNA and targeted by antisense oligonucleotides.

A preferential target of antisense oligonucleotides directed against human PGY/MDR1 mRNA is a hairpin containing a stem with a G*U wobble pair, capped by the purine-rich 5'r(GGGAUG)3' hexaloop. This hairpin is studied by multidimensional NMR and restrained molecular dynamics, with special emphasis on the conformation of south sugars and non-standard phosphate linkages evidenced in both the stem and the loop. The hairpin is found to be highly structured.

Quantification of DNA BI/BII backbone states in solution. Implications for DNA overall structure and recognition.

The backbone states of B-DNA influence its helical parameters, groove dimensions, and overall curvature. Therefore, detection and fine characterization of these conformational states are desirable. Using routine NMR experiments on a nonlabeled B-DNA oligomer and analyzing high-resolution X-ray structures, we investigated the relationship between interproton distances and backbone conformational states.

Different properties of H2O- and D2O-containing phospholipid-based reverse micelles near a critical temperature.

Dipalmitoylphosphatidylcholine (DPPC)/water/pyridine reverse micelles have been found to transform from a clear liquid into a glass when the DPPC-to-water volume fraction is in the 0.78-0.89 range at 28 or 26 degrees C depending on whether water is H2O or D2O.

Structure and dynamics of phosphate linkages and sugars in an abasic hexaloop RNA hairpin.

Hairpins containing hexaloops are well represented among the diverse conformations adopted by the RNA molecules. To investigate the intrinsic properties of a backbone submitted to a hexaloop fold, we present here a molecular dynamics study of an abasic hexaloop closed by an A-form 6 basepair stem. The analysis of the 23 ns trajectory made in explicit solvent shows that both the sugars and the torsion angles in the loop undergo numerous conformational transitions.

Serum 1H-nuclear magnetic spectroscopy followed by principal component analysis and hierarchical cluster analysis to demonstrate effects of statins on hyperlipidemic patients.

Use of statins for prevention of coronary heart disease is based on the decrease of serum cholesterol and LDL cholesterol. To better investigate the changes in lipid profile after statin treatment, we propose here to use an analysis of serum by proton nuclear magnetic resonance (NMR) spectroscopy associated with a multivariate analysis of the main spectral components. Sera were obtained from 60 male patients treated for 6 weeks with simvastatin (30 patients) or atorvastatin (30 patients) for who LDL cholesterol decreased by over 45% in all selected patients.

Impact of exogenous lysolipids on sensitive and multidrug resistant K562 cells: 1H NMR studies.

The ability of lysolipids to enter into a membrane bi-layer and disturb the membrane structure was used to study the behavior of K562 erythroleukemic cells, K562 wild type (K562wt) as well as the multidrug resistant cells K562adr. Both types of cells, when analyzed by proton NMR spectroscopy exhibit the high resolution signals assigned to so-called "mobile lipid" signals, which, in most cases, are located outside the lipid bi-layer as lipid droplets. In order to perform these studies, the K562wt and K562adr cells were treated for 48h with lysophosphatidylcholine oleoyl (LPC18), lysophosphatidylcholine palmitoyl (LPC16) and L-alpha-lysophosphatidyslerine (LPS).

N-acetyl functions and acetate detected by nuclear magnetic resonance spectroscopy of urine to detect renal dysfunction following aminoglycoside and/or glycopeptide antibiotic therapy.

Background/aims: N-acetylneuraminidine (NeuNAc), N-acetylglutamine (GIcNAc) and acetate are metabolites present in normal urine. In patients treated with aminoglycosides and/or glycopeptides, elevation of these metabolites in urine suggests renal tubular injury. NeuNAc, GIcNAc and acetate are easily detected by magnetic resonance spectroscopy (MRS), in contrast to other bioanalytical methods.

A hydroxyethylated cholesterol-based cationic lipid for DNA delivery: effect of conditioning.

We have synthesised a novel cholesterol-based cationic lipid to promote DNA transfer in cells. This lipid, dimethyl hydroxyethyl aminopropane carbamoyl cholesterol iodide (DMHAPC-Chol) contains a biodegradable carbamoyl linker and a hydroxyethyl group in the polar amino head moiety and is characterised by NMR. Liposomes prepared from this lipid and dioleoyl phosphatidyl ethanolamine (DOPE) in equimolar proportion showed a weak cytotoxicity as revealed by MTT assays and are efficient to deliver plasmids DNA evaluated by the expression of reporter genes in vitro and in vivo.

Aminoglycoside and glycopeptide renal toxicity in intensive care patients studied by proton magnetic resonance spectroscopy of urine.

Objective: Aminoglycoside and glycopeptide antibiotics are responsible for renal toxicity. In most cases, the nephrotoxicity is limited to a reversible tubular injury, but an acute and sustained renal failure may occur. The aim of our study was to explore the renal function of patients given these antimicrobial agents with proton magnetic resonance spectroscopy of urine.

Solution conformation of an RNA--DNA hybrid duplex containing a pyrimidine RNA strand and a purine DNA strand.

RNA--DNA hybrid duplexes are involved in transcription, replication and reverse transcription of nucleic acids. Information on such duplexes may shed some light on the mechanism of these processes. For this purpose, the influence of base composition on the structure of a polypyrimidine--polypurine RNA--DNA duplex r(cucuccuucucuu).

Magnetic resonance spectroscopy and fluorescence microscopy to investigate mobile lipids in sensitive, resistant and reverting K562 cells and their membranes.

The erythroleukaemic K562 cell line and its adriamycin resistant counterpart were used to study resistance, its reversion and their consequences on the levels and localisation of lipids detected in proton nuclear magnetic resonance (NMR) spectra. On whole cells, the mobile lipids giving rise to a NMR signal were significantly decreased in the resistant cells when compared to the sensitive ones; these lipids recovered partially in the reverting cells. According to the spinlattice relaxation times (T1), the lipids detected appeared to be in a similar environment in sensitive and reverting cells.

Current Awareness.

In order to keep subscribers up-to-date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of NMR in biomedicine. Each bibliography is divided into 9 sections: 1 Books, Reviews ' Symposia; 2 General; 3 Technology; 4 Brain and Nerves; 5 Neuropathology; 6 Cancer; 7 Cardiac, Vascular and Respiratory Systems; 8 Liver, Kidney and Other Organs; 9 Muscle and Orthopaedic.

Magnetic resonance spectroscopy of cellular lipid extracts from sensitive, resistant and reverting K562 cells and flow cytometry for investigating the P-glycoprotein function in resistance reversion.

The proton NMR spectra of K562 cells contain resonances of lipids. When these cells acquire multidrug resistance phenotype, the NMR lipid signals are modified and partially recovered when the resistance is reversed. The goals of the present study are to elucidate the mechanism of the resistance phenotype reversion and to investigate the possible origin of lipid signals detected in whole cells with proton NMR spectroscopy.