An Artificial Intelligence-Supported Medicinal Chemistry Project: An Example for Incorporating Artificial Intelligence Within the Pharmacy Curriculum.

Objective: This study aims to integrate and use AI to teach core concepts in a medicinal chemistry course and to increase the familiarity of pharmacy students with AI in pharmacy practice and drug development. Artificial intelligence (AI) is a multidisciplinary science that aims to build software tools that mimic human intelligence. AI is revolutionizing pharmaceutical research and patient care.

Pharmacokinetic model of human exposure to ciprofloxacin through consumption of fish.

Fluoroquinolones are broad-spectrum antibiotics that accumulate in the environment. To assess human exposure through the food chain, we developed a pharmacokinetic model of fluoroquinolone accumulation in fish and a human pharmacokinetic model to predict gastrointestinal concentrations of ciprofloxacin, a common fluoroquinolone, following consumption of fish. At 70 ng/L ciprofloxacin, the average in North American surface waters, the fish steady-state concentration was calculated to be 7.

Teaching of drug disposition using physiologically based pharmacokinetic modeling software: GastroPlus as an educational tool.

Physiologically based pharmacokinetic (PBPK) modeling requires an understanding of chemical, physiologic, and pharmacokinetic principles. Active learning with PBPK modeling software (GastroPlus) may be useful to teach these scientific principles while also teaching software operation. To examine this issue, a graduate-level course was designed using learning objectives in science, software use, and PBPK model application.

Prediction of Peptide and TCR CDR3 Loops in Formation of Class I MHC-Peptide-TCR Complexes Using Molecular Models with Solvation.

Formation of major histocompatibility (MHC)-peptide-T cell receptor (TCR) complexes is central to initiation of an adaptive immune response. These complexes form through initial stabilization of the MHC fold via binding of a short peptide, and subsequent interaction of the TCR to form a ternary complex, with contacts made predominantly through the complementarity-determining region (CDR) loops of the TCR. Stimulation of an immune response is central to cancer immunotherapy.

Assessment of the impact of co-curricular activities on achievement of Doctor of Pharmacy program outcomes.

Introduction: Co-curricular activities are recognized as an increasingly important aspect of pharmacy education. However, the impact of these activities on student learning is not well understood compared to that of curricular learning. The purpose of this study was to assess student-perceived progress in achieving program outcomes through voluntary co-curricular activities compared with learning of the same outcomes through mandatory curricular activities.

Prediction of Water Distributions and Displacement at Protein-Ligand Interfaces.

The retention and displacement of water molecules during formation of ligand-protein interfaces play a major role in determining ligand binding. Understanding these effects requires a method for positioning of water molecules in the bound and unbound proteins and for defining water displacement upon ligand binding. We describe an algorithm for water placement and a calculation of ligand-driven water displacement in >9000 protein-ligand complexes.

Integration of Clinical and Scientific Principles in the Teaching of Drug-Drug Interactions.

Evaluation of drug-drug interactions (DDIs) is an integral part of pharmacy practice worldwide. An understanding of the scientific mechanisms behind and the clinical implications of DDIs is important for proper management of pharmacotherapy. Here, we describe an integrated approach to teaching both aspects of DDIs as a standalone module in diverse course settings.

Lysine acetylation regulates the interaction between proteins and membranes.

Lysine acetylation regulates the function of soluble proteins in vivo, yet it remains largely unexplored whether lysine acetylation regulates membrane protein function. Here, we use bioinformatics, biophysical analysis of recombinant proteins, live-cell fluorescent imaging and genetic manipulation of Drosophila to explore lysine acetylation in peripheral membrane proteins. Analysis of 50 peripheral membrane proteins harboring BAR, PX, C2, or EHD membrane-binding domains reveals that lysine acetylation predominates in membrane-interaction regions.

Ligand-specific pharmacogenetic effects of nonsynonymous mutations.

In pharmacogenomics, variable receptor phenotypes, resulting from genetic polymorphisms, are often described as a change in protein function or regulation observed upon exposure to a drug. However, in some instances, phenotypes are defined using a class of medications rather than individual drugs. This paradigm assumes that a variation associated with a drug response phenotype will retain the magnitude and direction of the effect for other drugs with the same mechanism of action.

Corrigendum to "Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression" [Heliyon 5 (3) (March 2019) e01366].

[This corrects the article DOI: 10.1016/j.heliyon.

Experimental Validation of the ALLNOX Program for Studying Protein-Nucleic Acid Complexes.

Measurement of distances between spectroscopic labels (e.g., spin labels, fluorophores) attached to specific sites of biomolecules is an important method for studying biomolecular complexes.

Naturally occurring sesquiterpene lactones and their semi-synthetic derivatives modulate PGE2 levels by decreasing COX2 activity and expression.

Plants of the Asteraceae family have been used in traditional medicine for centuries due to their main antimicrobial and analgesic activities. A liniment from has recently been tested on patients affected by either acute pain or chronic pain conditions with great success. The aim of this study was to evaluate the anti-inflammatory activity of sesquiterpene lactones (SLs), representing the majority in the Asteraceae family.

A curcumin-diglutaric acid conjugated prodrug with improved water solubility and antinociceptive properties compared to curcumin.

In this work, a curcumin-diglutaric acid (CurDG) prodrug was synthesized by conjugation of curcumin with glutaric acid via an ester linkage. The water solubility, partition coefficient, release characteristics, and antinociceptive activity of CurDG were compared to those of curcumin. The aqueous solubility of CurDG (7.

Rational drug design and synthesis of new α-Santonin derivatives as potential COX-2 inhibitors.

Sesquiterpene compounds are widely known for their numerous pharmacological activities. Herein the focus of the authors was on α-Santonin, a sesquiterpene lactone from the Artemisia genus: the aim was to determine whether α-Santonin could be considered in the treatment of inflammation and pain. To this purpose, a small series of derivatives was designed and screened in silico against the enzyme COX-2 along with the parent compound.

Physiologically Based Pharmacokinetic Modeling in Lead Optimization. 1. Evaluation and Adaptation of GastroPlus To Predict Bioavailability of Medchem Series.

When medicinal chemists need to improve bioavailability (%F) within a chemical series during lead optimization, they synthesize new series members with systematically modified properties mainly by following experience and general rules of thumb. More quantitative models that predict %F of proposed compounds from chemical structure alone have proven elusive. Global empirical %F quantitative structure-property (QSPR) models perform poorly, and projects have too little data to train local %F QSPR models.

Physiologically Based Pharmacokinetic Modeling in Lead Optimization. 2. Rational Bioavailability Design by Global Sensitivity Analysis To Identify Properties Affecting Bioavailability.

When medicinal chemists need to improve oral bioavailability (%F) during lead optimization, they systematically modify compound properties mainly based on their own experience and general rules of thumb. However, at least a dozen properties can influence %F, and the difficulty of multiparameter optimization for such complex nonlinear processes grows combinatorially with the number of variables. Furthermore, strategies can be in conflict.

Enhancement of Curcumin Bioavailability Via the Prodrug Approach: Challenges and Prospects.

Curcumin is a natural product with many interesting pharmacological properties. However, these are offset by the particularly poor biopharmaceutical properties. The oral bioavailability of curcumin in humans is very low, mainly due to low solubility, poor stability, and extensive metabolism.

Computer Modeling of Spin Labels: NASNOX, PRONOX, and ALLNOX.

Measurement of distances between spin labels using electron paramagnetic resonance with the double electron-electron resonance (DEER) technique is an important method for evaluation of biomolecular structures. Computation of interlabel distances is of value for experimental planning, validation of known structures using DEER-measured distances, and determination of theoretical data for comparison with experiment. This requires steps of building labels at two defined sites on proteins, DNA or RNA; calculation of allowable label conformers based on rotation around torsional angles; computation of pairwise interlabel distances on a per conformer basis; and calculation of an average distance between the two label ensembles.

An Integrated Spin-Labeling/Computational-Modeling Approach for Mapping Global Structures of Nucleic Acids.

The technique of site-directed spin labeling (SDSL) provides unique information on biomolecules by monitoring the behavior of a stable radical tag (i.e., spin label) using electron paramagnetic resonance (EPR) spectroscopy.

Structural Characterization of Membrane-Curving Proteins: Site-Directed Spin Labeling, EPR, and Computational Refinement.

Endocytosis and other membrane remodeling processes require the coordinated generation of different membrane shapes. Proteins capable of manipulating lipid bilayers mediate these events using mechanisms that are not fully understood. Progress is limited by the small number of structures solved for proteins bound to different membrane shapes and tools capable of resolving such information.

The role of the C-terminal helix of U1A protein in the interaction with U1hpII RNA.

Previous kinetic investigations of the N-terminal RNA Recognition Motif (RRM) domain of spliceosomal A protein of the U1 small nuclear ribonucleoprotein particle (U1A) interacting with its RNA target U1 hairpin II (U1hpII) provided experimental evidence for a 'lure and lock' model of binding. The final step of locking has been proposed to involve conformational changes in an α-helix immediately C-terminal to the RRM domain (helix C), which occludes the RNA binding surface in the unbound protein. Helix C must shift its position to accommodate RNA binding in the RNA-protein complex.

Electrophoretic mobility of duplex DNA cross-linked by mechlorethamine at a cytosine-cytosine mismatch pair.

The common nitrogen mustard, mechlorethamine, can form a covalent cross-link between the two bases of a cytosine-cytosine mismatch pair within a DNA duplex. The cross-linked species can be readily separated from DNA monoadducts and unreacted strands using denaturing polyacrylamide gel electrophoresis. Here, using DNA 19 mer duplexes that are mechlorethamine cross-linked at a C(4)-C(35), C(7)-C(32), C(10)-C(29), or C(13)-C(26) mismatch pair, we show that the denaturing polyacrylamide gel electrophoresis mobility of the cross-linked species is particularly sensitive to the proximity of the C-C cross-link to the duplex end.

Idealized models of protofilaments of human islet amyloid polypeptide.

Fibrils formed by assembly of human islet amyloid polypeptide (hIAPP) are found in most patients with type II diabetes. Structurally, these fibrils are composed of multiple protofilaments and are characterized by extended beta sheets, variable helical twists, and different morphologies. We have previously derived models for the hIAPP protofilament using simulations constrained by data from EPR spectroscopy.

Nitroxide sensing of a DNA microenvironment: mechanistic insights from EPR spectroscopy and molecular dynamics simulations.

The behavior of the nitroxide spin labels 1-oxyl-4-bromo-2,2,5,5-tetramethylpyrroline (R5a) and 1-oxyl-2,2,5,5-tetramethylpyrroline (R5) attached at a phosphorothioate-substituted site in a DNA duplex is modulated by the DNA in a site- and stereospecific manner. A better understanding of the mechanisms of R5a/R5 sensing of the DNA microenvironment will enhance our capability to relate information from nitroxide spectra to sequence-dependent properties of DNA. Toward this goal, electron paramagnetic resonance (EPR) spectroscopy and molecular dynamics (MD) simulations were used to investigate R5 and R5a attached as R(p) and S(p) diastereomers at phosphorothioate (pS)C(7) of d(CTACTG(pS)C(7)Y(8)TTAG).

Information intervention in the pharmaceutical sciences.

Professional guidelines state that higher-order thinking skills are a desirable outcome of pharmacy education. In this context, courses in pharmaceutics at the University of Southern California are taught in a learner-centered manner that requires use of chemical reference sources and interpretation of physicochemical information for drug molecules. To facilitate these activities, a librarian worked with faculty to design a class on reference sources and primary literature.