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Background: Conventional de novo drug design is costly and time consuming, making it accessible to only the best resourced research organizations. An emergent approach to new drug development is drug repurposing, in which compounds that have already gone through some level of clinical testing are examined for efficacy against diseases divergent than their original application. Repurposing of existing drugs circumvents the time and considerable cost of early stages of drug development, and can be accelerated by using software to screen existing chemical databases to identify suitable drug candidates. Results: Small-molecule Peptide-Influenced Drug Repurposing (SPIDR) was developed to identify small molecule drugs that target a specific receptor by exploring the conformational binding space of peptide ligands. SPIDR was tested using the potent and selective 16-amino acid peptide α-conotoxin MII ligand and the α3β2-nicotinic acetylcholine receptor (nAChR) isoform. SPIDR incorporates a genetic algorithm-based, heuristic search procedure, which was used to explore the ligand binding domain of the α3β2-nAChR isoform using a library consisting of 640,000 α-conotoxin MII peptide analogs. The peptides that exhibited the highest affinity for α3β2-nAChR were used as models for a small-molecule structure similarity search of the PubChem Compound database. SPIDR incorporates the SimSearcher utility, which generates shape distribution signatures of molecules and employs multi-level K-means clustering to insure fast database queries. SPIDR identified non-peptide drugs with estimated binding affinities nearly double that of the native α-conotoxin MII peptide. Conclusions: SPIDR has been generalized and integrated into DockoMatic v 2.1. This software contains an intuitive graphical interface for peptide mutant screening workflow and facilitates mapping, clustering, and searching of local molecular databases, making DockoMatic a valuable tool for researchers in drug design and repurposing. [ABSTRACT FROM AUTHOR]

Modified cytosine and guanine nucleobases cocrystallize in a hydrogen bonding configuration similar to that observed in native DNA. The noncovalent interactions binding these base pairs in the crystalline solid were investigated using terahertz (THz) spectroscopy and solid-state density functional theory (DFT). While stronger hydrogen bonding interactions are responsible for the general molecular orientations in the crystalline state, it is the weaker dipole-dipole and dispersion forces that determine the overall packing arrangement. The inclusion of dispersion interactions in the DFT calculations was found to be necessary to accurately simulate the unit cell structure and THz vibrational spectrum. Using properly modeled intermolecular potentials, the lattice vibrational motions of the cytosine and guanine derivatives were calculated. The vibrational characters of the modes exhibited by the DNA base pair mimic in the THz region were primarily rotational motions and are indicative of the energies and the nature of vibrations that would likely be observed between similar base pairs in DNA molecules. [ABSTRACT FROM AUTHOR]

Cocrystallized adenine and thymine derivatives, along with the pure monomeric crystals, were investigated by terahertz spectroscopy and solid-state density functional theory (DFT). The methylated nudeobase derivatives crystallize in planar hydrogen-bonded adenine-thymine pairs similar to the manner found in DNA. The spectra obtained for 1-methylthy- mine, 9-methyladenine, and the 1:1 cocrystal in the range of 10-100 cm-1 clearly demonstrate that absorptions in this spectral range originate from the uniquely ordered assembly and the intermolecular interactions found in each individual crystal system. The quality of spectral reproduction for the DFT simulations of each system was dearly improved by the indusion of an empirical correction term for London-type dispersion forces to the calculations. Notably, it was found that these weak dispersion forces in the adenine-thymine cocrystal were necessary to produce a properly converged crystal structure and meaningful simulation of the terahertz vibrational spectrum. [ABSTRACT FROM AUTHOR]

Polymorph detection and quantification in crystalline materials is a principle interest of the pharmaceutical industry. Terahertz (THz) spectroscopy can be used for such analytical applications since this technique is sensitive to the intermolecular interactions of molecules in the solid state. Understanding the fundamental nature of the lattice vibrational motions leading to absorptions in THz spectra is challenging, but may be achieved through computational approaches. In this study, the THz spectra of two diclofenac acid polymorphs were obtained by THz spectroscopy, and the vibrational characters of the observed absorptions were analyzed using solid-state density functional theory (DFT). The results demonstrate the quantitative capacity of THz spectroscopy and the reliability and utility of solid-state DFT in the calculation of low-frequency vibrational motions. [ABSTRACT FROM AUTHOR]

The potential applications of terahertz (THz) spectroscopy in the analysis of pharmaceutical products in their crystalline state have prompted the need for a more thorough understanding of the fundamental vibrational motions contributing to the THz spectra. The detection of variations in crystal structure and the reliable assignment of observed THz absorption features can be aided by the use of solid-state density functional theory (DFT). In this study, solid-state DFT with periodic boundary conditions was used to simulate the crystalline structure and assign the experimental THz spectra (10-90 cm) of the enantiomerically pure and racemic forms of the common pharmaceutical compound ibuprofen. The results clearly demonstrate the capabilities of DFT methodologies to accurately reproduce the THz spectra of large complicated molecular systems and provide insight into the internal and external vibrational motions that form the basis of THz spectroscopy. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1116-1129, 2011 [ABSTRACT FROM AUTHOR]

Temperature and velocity fields in a downward flame spread over flat, solid fuels in a gravitational field are numerically simulated and compared with available experimental measurements and a simplified theory. The two-dimensional steady numerical model solves the mass, energy, species-mass, and momentum equations in the gaseous phase and the energy equation in the solid phase and includes gas-phase and pyrolysis kinetics, gas and surface radiation with radiation feedback. The published experimental results include measured temperature and velocity profiles, surface regression data, visible images of flames, and images taken with interferometers. A simplified parabolic solution for the temperature field in an opposed-flow configuration is extended to the downward configuration and compared with the simulation and experimental results. Flames over thin cellulosic fuels and PMMA, both in the thick and thin limits are considered. With one exception, the numerical model is found to reproduce the observed flame structure for a diverse range of fuel and ambient conditions. The simplified theory, based on a parabolic solution of the coupling functions, is found to reproduce the temperature fields in the gas and the solid reasonably well for flame spreads over thick fuels. [ABSTRACT FROM AUTHOR]

Accurate interpretations of THz vibrational spectra using density functional theory (DFT) must account for the often significant thermal expansion exhibited by molecular crystal systems. In this study, the THz spectra of two p-nitrophenol polymorphs were obtained in the spectral bandwidth of 20–95 cm−1, and solid-state DFT was used to assign the observed absorptions to specific vibrational mode characters. Computational treatments of the crystal systems involved comparison of phonon frequencies produced from both fixed- and full-unit cell geometry optimizations using a variety of functional and basis set combinations. Arbitrary frequency scaling was applied to overcome the temperature dependence of unit cell volumes and associated phonon vibrational frequencies. Fully relaxed cell geometries producing contracted cell volumes resulted in a large overestimation of THz vibrational frequencies. Employing appropriate frequency scaling factors to the computed mode frequencies allowed for proper vibrational mode assignments and enhanced the quality of spectral simulations versus fixed-cell calculations. Optimal frequency scalars in the range of 0.675 to 0.827 were determined to best reproduce the THz spectra of the p-nitrophenol polymorphs. This treatment of calculated phonon modes offers the key advantage of eliminating the temperature correlation between the crystal structure data and the THz data acquisition. [ABSTRACT FROM AUTHOR]

Fortilin is a 172-amino acid multifunctional protein present in both intra- and extracellular spaces. Although fortilin binds and regulates various cellular proteins, the biological role of extracellular fortilin remains unknown. Here we report that fortilin specifically interacts with TGF-β1 and prevents it from activating the TGF-β1 signaling pathway. In a standard immunoprecipitation-western blot assay, fortilin co-immunoprecipitates TGF-β1 and its isoforms. The modified ELISA assay shows that TGF-β1 remains complexed with fortilin in human serum. Both bio-layer interferometry and surface plasmon resonance (SPR) reveal that fortilin directly bind TGF-β1. The SPR analysis also reveals that fortilin and the TGF-β receptor II (TGFβRII) compete for TGF-β1. Both luciferase and secreted alkaline phosphatase reporter assays show that fortilin prevents TGF-β1 from activating Smad3 binding to Smad-binding element. Fortilin inhibits the phosphorylation of Smad3 in both quantitative western blot assays and ELISA. Finally, fortilin inhibits TGFβ-1-induced differentiation of C3H10T1/2 mesenchymal progenitor cells to smooth muscle cells. A computer-assisted virtual docking reveals that fortilin occupies the pocket of TGF-β1 that is normally occupied by TGFβRII and that TGF-β1 can bind either fortilin or TGFβRII at any given time. These data support the role of extracellular fortilin as a negative regulator of the TGF-β1 signaling pathway. Fortilin prevents the activation of the TGF-β1 receptor by occupying the pocket of TGF-β1 and competing with TGF-βRII to bind with TGF-β1. This inhibits Smad3 phosphorylation and the differentiation of C3H10T1/2 mesenchymal progenitor cells to smooth muscle cells. [ABSTRACT FROM AUTHOR]

Since the discovery of penicillin, the development and use of antibiotics have promoted safe and effective control of bacterial infections. However, the number of antibiotic-resistance cases has been ever increasing over time. Thus, the drug discovery process demands fast, efficient and cost-effective alternative approaches for developing lead candidates with outstanding performance. Computational approaches are appealing techniques to develop lead candidates in an in silico fashion. In this review, we provide an overview of the implementation of current in silico state-of-the-art techniques, including machine learning (ML) and deep learning (DL), in drug discovery. We also discuss the development of quantum computing and its potential benefits for antibiotics research and current bottlenecks that limit computational drug discovery advancement. [ABSTRACT FROM AUTHOR]

Background: Repeatability and validity are important components of precision in any measurement system. Aim: This study aimed to determine the effect of change in head and neck position and body posture on the repeatability of intraocular pressure (IOP) measurements with PT-100 non-contact tonometer and compare with Goldmann, PT-100 and Schiøtz tonometer readings. Setting: Optometry clinic, Saudi Arabia. Methods: The IOP was measured in one selected eye of 84 healthy participants (mean aged 21.9 ± 2.0 years) using PT-100 in three head and body positions, Goldmann tonometer and Schiøtz on two separate visits, in a randomised fashion. Central corneal thickness (CCT) was measured using an ultrasound pachymeter. The repeatability, agreement and correlations between CCT and IOP differentials were assessed. Results: The IOP measured in three head and body positions with the PT-100 were similar and comparable to Goldmann IOPs in sessions one and two with 74% and 86% of PT-100 measurements within ±3 mmHg of the Goldmann tonometry, respectively, for sessions one and two. The Schiøtz tonometer-measured IOP was higher than the Goldmann IOPs (p < 0.05) with 60% and 44% of Schiøtz IOPs within ±3 mmHg of the Goldmann tonometer IOP in sessions one and two, respectively. The limits of repeatability and reproducibility were best with the PT-100 and worst with the Schiøtz tonometer. The mean CCT (552±36 µm) was negatively correlated with differences between Goldmann and both PT-100 and Schiøtz-measured IOP. Conclusion: Postural changes did not affect the validity and repeatability of PT-100 readings. PT-100 measurements were interchangeable with Goldmann tonometer. Schiøtz overestimated Goldmann IOP in thicker corneas more than the PT-100. [ABSTRACT FROM AUTHOR]

Oncostatin M (OSM) is a pleiotropic, interleukin-6 family inflammatory cytokine that plays an important role in inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, and cancer progression and metastasis. Recently, elevated OSM levels have been found in the serum of COVID-19 patients in intensive care units. Multiple anti-OSM therapeutics have been investigated, but to date no OSM small molecule inhibitors are clinically available. To pursue a high-throughput screening and structure-based drug discovery strategy to design a small molecule inhibitor of OSM, milligram quantities of highly pure, bioactive OSM are required. Here, we developed a reliable protocol to produce highly pure unlabeled and isotope enriched OSM from E. coli for biochemical and NMR studies. High yields (ca. 10 mg/L culture) were obtained in rich and minimal defined media cultures. Purified OSM was characterized by mass spectrometry and circular dichroism. The bioactivity was confirmed by induction of OSM/OSM receptor signaling through STAT3 phosphorylation in human breast cancer cells. Optimized buffer conditions yielded 1H, 15N HSQC NMR spectra with intense, well-dispersed peaks. Titration of 15N OSM with a small molecule inhibitor showed chemical shift perturbations for several key residues with a binding affinity of 12.2 ± 3.9 μM. These results demonstrate the value of bioactive recombinant human OSM for NMR-based small molecule screening. [ABSTRACT FROM AUTHOR]

Veratrum californicum , commonly referred to as corn lily or Californian false hellebore, grows in high mountain meadows and produces the steroidal alkaloid cyclopamine, a potent inhibitor of the Hedgehog (Hh) signaling pathway. The Hh pathway is a crucial regulator of many fundamental processes during vertebrate embryonic development. However, constitutive activation of the Hh pathway contributes to the progression of various cancers. In the present study, a direct correlation was made between the extraction efficiency for cyclopamine from root and rhizome by eight methods, and the associated biological activity in Shh-Light II cells using the Dual-Glo® Luciferase Assay System. Alkaloid recovery ranged from 0.39 to 8.03 mg/g, with ethanol soak being determined to be the superior method for obtaining biologically active cyclopamine. Acidic ethanol and supercritical extractions yielded degraded or contaminated cyclopamine with lower antagonistic activity towards Hh signaling. [ABSTRACT FROM AUTHOR]