Chemistry Program Research Articles

Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform.

STUDY QUESTIONCan a high-throughput screening (HTS) platform facilitate male fertility drug discovery?SUMMARY ANSWERAn HTS platform identified a large number of compounds that enhanced sperm motility.WHAT IS KNOWN ALREADYSeveral efforts to find small molecules modulating sperm function have been performed but none have used high-throughput technology.STUDY DESIGN, SIZE, DURATIONHealthy donor semen samples were used and samples were pooled (3–5 donors per pool). Primary screening was performed singly; dose–response screening was performed in duplicate (using independent donor pools).PARTICIPANTS/MATERIALS, SETTING, METHODSSpermatozoa isolated from healthy donors were prepared by density gradient centrifugation and incubated in 384-well plates with compounds (6.25 μM) to identify those compounds with enhancing effects on motility. Approximately 17 000 compounds from the libraries, ReFRAME, Prestwick, Tocris, LOPAC, CLOUD and MMV Pathogen Box, were screened. Dose–response experiments of screening hits were performed to confirm the enhancing effect on sperm motility. Experiments were performed in a university setting.MAIN RESULTS AND THE ROLE OF CHANCEFrom our primary single concentration screening, 105 compounds elicited an enhancing effect on sperm motility compared to dimethylsulphoxide-treated wells. Confirmed enhancing compounds were grouped based on their annotated targets/target classes. A major target class, phosphodiesterase inhibitors, were identified, in particular PDE10A inhibitors as well as number of compounds not previously known to enhance human sperm motility, such as those related to GABA signalling.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONAlthough this approach provides data about the activity of the compound, it is only a starting point. For example, further substantive experiments are necessary to provide a more comprehensive picture of each compound’s activity, the effect on the kinetics of the cell populations and subpopulations, and their potential mechanisms of action. Compounds have been tested with prepared donor spermatozoa, incubated under non-capacitating conditions, and only incubated with compounds for a relatively short period of time. Therefore, the effect of compounds under different conditions, for example in whole semen, for longer incubation times, or using samples from patient groups, may be different and require further study. All experiments were performed in vitro.WIDER IMPLICATIONS OF THE FINDINGSThis phenotypic screening assay identified a large number of compounds that increased sperm motility. In addition to furthering our understanding of human sperm function, for example identifying new avenues for discovery, we highlight potential compounds as promising start-point for a medicinal chemistry programme for potential enhancement of male fertility. Moreover, with disclosure of the results of screening, we present a substantial resource to inform further work in the field.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Bill and Melinda Gates Foundation, Scottish Funding Council and Scottish Universities Life Science Alliance. C.L.R.B. is Editor for RBMO. C.L.R.B. receives funding from Chief Scientists Office (Scotland), ESHRE and Genus PLC, consulting fees from Exscientia and lecture fees from Cooper Surgical and Ferring. S.M.d.S. is an Associate Editor of Human Reproduction, and an Associate Editor of Reproduction and Fertility. S.M.d.S. receives funding from Cooper Surgical and British Dietetic Society. No other authors declared a COI.

Ultra-fast microscale purification of chiral racemates and achiral pharmaceuticals with analytical supercritical fluid chromatography

Improving efficiency while maintaining high quality separations is a central theme for specialized analytical/purification groups supporting discovery chemistry programs. Supercritical fluid chromatography (SFC) has become the prevalent technique for chiral separation and a complementary technique to reverse phase high-pressure liquid chromatography (RP-HPLC). In this manuscript we demonstrate the successful micro-isolation of chiral racemates, small molecules, and peptides using a sub-minute method on an analytical SFC system. The addition of a custom gas liquid separator (GLS) and alterations to the fluidic pathways allow the fractionation of desired products on a micro-scale SFC platform, providing analytical method development, purifications, and purity confirmation on a single SFC system. This enables micro-purification of pharmaceuticals including chiral racemates at high speed and reduced cost of materials. The resulting small-quantity, high-purity products enable follow-up enantioselective isolations from racemic products of parallel synthesis libraries. The processes established here will be beneficial for the isolations of other desired products in complex crude mixtures.

Self-regulated learning of Natural Sciences and Mathematics future teachers: Learning strategies, self-efficacy, and socio-demographic factors

Teacher education programs should have as one of their purposes the promotion of self-regulatory skills for learning among students who aspire to be teachers so that they can take a leading role in their learning and foster these skills in their future students. Considering the importance of knowing what students in teacher education programs do to study and learn, as well as how efficacious they feel to deal with academic demands, this study is part of a larger research and aims to investigate the learning and study strategies and self-efficacy for learning beliefs of 220 students enrolled in teacher education programs in Biological Sciences, Chemistry, Physics and Mathematics of a Higher Education Institution in the state of Piauí, and examine them in relation to age, gender, licentiate area, and course semester. Brazilian translations of the Learning and Study Strategies Inventory (LASSI — Third Edition) and the Self-efficacy for Learning Form were used for data collection. Scales were administered in the classrooms both through online platforms and in paper and pencil. Nonparametric inferential statistical approaches were used to test hypotheses regarding group differences. Statistically significant differences were found in LASSI in relation to gender, licentiate area, and course semester. Overall, students in Physics dealt better with anxiety; in Mathematics showed more favorable attitudes towards learning; in Chemistry reported managing their time better; in Biological Science showed significantly lower scores on many scales than did other students. Findings from this study could help inform curricular design decisions regarding teacher education programs and inform the design of interventions to strengthen the learning and study strategies and the self-efficacy for learning beliefs of future teachers.

SAMPLE WORK PROGRAM IN CHEMISTRY: ONE STEP FORWARD, TWO STEPS BACK

The article gives a critical analysis of the content and structure of the exemplary work program in chemistry for the basic school (grades 8–9). It is proved that the construction of a chemistry course on the basis of this program returns school chemical education to several decades ago.

Student perspectives on online lectures during the Covid-19 lockdown

This article outlines an exploratory study that investigated students’ perceptions of the benefits and disadvantages of lecture recordings delivered as part of an introductory chemistry program in the UK during the COVID-19 lockdown in Spring 2020. Three features of these lecture recordings are considered: 1) the production of a series of mini-lectures rather than 50 minute recordings; 2) the inclusion of quiz questions in the video timeline; and 3) the inclusion of a picture-in-picture talking head showing the instructor alongside a captured screen. Analysis of survey data indicates that a majority of students felt that each of these features had a positive impact on their learning and/or experience, with a significant number expressing a preference for the retention of online lectures after the resumption of on-campus teaching. Qualitative data provides valuable insight regarding the specific aspects of the recorded lectures that were perceived to enhance the student experience, supporting the design of future provision both during and beyond the COVID-19 pandemic. The generalizability of the recommendations is also discussed, along with the limitations of the study.

Morphological profiling by means of the Cell Painting assay enables identification of tubulin-targeting compounds

In phenotypic compound discovery, conclusive identification of cellular targets and mode of action are often impaired by off-target binding. In particular, microtubules are frequently targeted in cellular assays. However, invitro tubulin binding assays do not correctly reflect the cellular context, and conclusive high-throughput phenotypic assays monitoring tubulin binding are scarce, such that tubulin binding is rarely identified. We report that morphological profiling using the Cell Painting assay (CPA) can efficiently detect tubulin modulators in compound collections with a high throughput, including annotated reference compounds and unannotated compound classes with unrelated chemotypes and scaffolds. Small-molecule tubulin binders share similar CPA fingerprints, which enables prediction and experimental validation of microtubule-binding activity. Our findings suggest that CPA or a related morphological profiling approach will be an invaluable addition to small-molecule discovery programs in chemical biology and medicinal chemistry, enabling early identification of one of the most frequently observed off-target activities.

Explainable Machine Learning for Property Predictions in Compound Optimization.

The prediction of compound properties from chemical structure is a main task for machine learning (ML) in medicinal chemistry. ML is often applied to large data sets in applications such as compound screening, virtual library enumeration, or generative chemistry. Albeit desirable, a detailed understanding of ML model decisions is typically not required in these cases. By contrast, compound optimization efforts rely on small data sets to identify structural modifications leading to desired property profiles. In this situation, if ML is applied, one usually is reluctant to make decisions based on predictions that cannot be rationalized. Only few ML methods are interpretable. However, to yield insights into complex ML model decisions, explanatory approaches can be applied. Herein, methodologies for better understanding of ML models or explaining individual predictions are reviewed and current challenges in integrating ML into medicinal chemistry programs as well as future opportunities are discussed.

Development of small‐molecule tau‐SH3 interaction inhibitors that prevent amyloid‐β toxicity

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia and lacks disease‐modifying treatments. Tau‐based therapies are attractive and Tau reduction prevents amyloid‐induced dysfunction in preclinical AD models. Tau reduction also prevents amyloid‐independent dysfunction in diverse disease contexts, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau’s interaction with SH3 domain containing proteins likely underlie mechanisms of amyloid‐induced dysfunction, so we targeted their interaction as a therapeutic strategy.MethodWe previously designed a peptide Tau‐SH3 interaction inhibitor based on the region of Tau that binds FynSH3, and determined that it prevented amyloid‐induced dysfunction in primary neurons. We next completed a high‐throughput screen to identify compounds that inhibit Tau‐Fyn interaction. Here, we studied a top hit from that screen, generated and characterized a series of daughter compounds, and tested whether the compounds prevented amyloid‐induced dysfunction in primary neurons.ResultThe hit compound, SR31627, prevented amyloid‐β toxicity in primary neurons. The medicinal chemistry program resulted in lead compound SR42667, which had five‐fold improved potency and improved drug‐like properties. We found that SR42667 binds Tau, is cell‐permeable, and prevents amyloid‐induced dysfunction.ConclusionWe demonstrate that Tau‐SH3 interactions can be targeted using small molecule inhibitors and that these inhibitors have efficacy for blocking amyloid‐induced dysfunction.

Binary-Encounter Model for Direct Ionization of Molecules by Positron-Impact

We introduce two models for the computation of direct ionization cross sections by positron impact over a wide range of collision energies. The models are based on the binary-encounter-Bethe model and take into account an extension of the Wannier theory. The cross sections computed with these models show good agreement with experimental data. The extensions improve the agreement between theory and experiment for collision energies between the first ionization threshold and the peak of the cross section. The models are based on a small set of parameters, which can be computed with standard quantum chemistry program packages.

Quantum Chemistry Common Driver and Databases (QCDB) and Quantum Chemistry Engine (QCEngine): Automation and interoperability among computational chemistry programs.

Community efforts in the computational molecular sciences (CMS) are evolving toward modular, open, and interoperable interfaces that work with existing community codes to provide more functionality and composability than could be achieved with a single program. The Quantum Chemistry Common Driver and Databases (QCDB) project provides such capability through an application programming interface (API) that facilitates interoperability across multiple quantum chemistry software packages. In tandem with the Molecular Sciences Software Institute and their Quantum Chemistry Archive ecosystem, the unique functionalities of several CMS programs are integrated, including CFOUR, GAMESS, NWChem, OpenMM, Psi4, Qcore, TeraChem, and Turbomole, to provide common computational functions, i.e., energy, gradient, and Hessian computations as well as molecular properties such as atomic charges and vibrational frequency analysis. Both standard users and power users benefit from adopting these APIs as they lower the language barrier of input styles and enable a standard layout of variables and data. These designs allow end-to-end interoperable programming of complex computations and provide best practices options by default.

Pharmacological characterisation of GSK3335103, an oral αvβ6 integrin small molecule RGD-mimetic inhibitor for the treatment of fibrotic disease

Fibrosis is the formation of scar tissue due to injury or long-term inflammation and is a leading cause of morbidity and mortality. Activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ) via the alpha-V beta-6 (αvβ6) integrin has been identified as playing a key role in the development of fibrosis. Therefore, a drug discovery programme to identify an orally bioavailable small molecule αvβ6 arginyl-glycinyl-aspartic acid (RGD)-mimetic was initiated. As part of a medicinal chemistry programme GSK3335103 was identified and profiled in a range of pre-clinical in vitro and in vivo systems. GSK3335103 was shown to bind to the αvβ6 with high affinity and demonstrated fast binding kinetics. In primary human lung epithelial cells, GSK3335103-induced concentration- and time-dependent internalisation of αvβ6 with a rapid return of integrin to the cell surface observed after washout. Following sustained engagement of the αvβ6 integrin in vitro, lysosomal degradation was induced by GSK3335103. GSK3335103 was shown to engage with the αvβ6 integrin and inhibit the activation of TGFβ in both ex vivo IPF tissue and in a murine model of bleomycin-induced lung fibrosis, as measured by αvβ6 engagement, TGFβ signalling and collagen deposition, with a prolonged duration of action observed in vivo. In summary, GSK3335103 is a potent αvβ6 inhibitor that attenuates TGFβ signalling in vitro and in vivo with a well-defined pharmacokinetic/pharmacodynamic relationship. This translates to a significant reduction of collagen deposition in vivo and therefore GSK3335103 represents a potential novel oral therapy for fibrotic disorders.

Guidelines for Advancing Diversity, Equity, Inclusion, and Respect in Programs Offering Bachelor’s Degrees in Chemistry

The chemical enterprise is recognizing that inclusive and equitable environments are essential to its mission and advancement. As such, the education and training of chemists requires a reassessment of how academic programs integrate diversity, equity, and inclusion (DEI) as a core principle of educational quality. This article describes a 3-year process that resulted in integrating experiences, ideas, priorities, and feedback from the chemistry community into a set of guidelines that agrees with the American Chemical Society (ACS)’s core value of diversity, equity, inclusion, and respect (DEIR). The process included learning about current DEI practices through a focus group, surveying stakeholders about the role of DEI in chemistry education, bringing together department chairpersons from all types of academic institutions from across the nation to discuss how they would adapt to DEIR guidelines, and synthesis of the DEIR guidelines that will be incorporated into the ACS Guidelines for Bachelor’s Degree Programs. The guidelines, described in this article, provide a DEIR baseline to maintain ACS Approval (critical requirements), direct programs to support and develop a DEIR culture (normal expectations), and exhort programs to make DEIR a priority (markers of excellence). It is anticipated that the DEIR guidelines will promote a DEIR culture among chemistry programs and that these guidelines could be adapted to other disciplines and organizations.

Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce c-MYC Protein Levels in Cells.

Elevated expression of the c-MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous c-MYC protein levels in a MYC-amplified cell line led to the discovery of a compound series that phenocopies c-MYC knockdown by siRNA. Herein, we describe our medicinal chemistry program that led to the discovery of potent, orally bioavailable c-MYC-reducing compounds. The development of a minimum pharmacophore model based on empirical structure activity relationship as well as the property-based approach used to modulate pharmacokinetics properties will be highlighted.

Emotional, Attitude and Classroom Action Research Competency Conduction of Undergraduate Students Through STEM Education

The purposes of this research were: 1) to develop lesson plans for STEM education for undergraduate students with the efficiency of the processing performances and the performance results (E1/E2) at the determining criteria as 75/75, 2) to compare emotional, attitude towards research, and classroom action research competency of undergraduate students before and after implementing STEM education. The sample was one class of the teaching profession program in Chemistry. The experimental group was selected by simple random sampling. The research instrument was lesson plans for STEM education management and practical skill development, a test of research knowledge, a research skill assessment form, an observation form, and a questionnaire. The statistics used were the percentage, mean, standard deviation, and Multivariate Paired Hotelling’s T-Square. The research results showed that 1) the efficiency of the STEM lesson plans for undergraduate students’ processing performances was 87.12 percent, and the performance results were 74.17 percent (87.12/74.17), meeting the set criteria of 75/75, 2) students had emotional, attitude towards research and classroom action research competency conduction after implementing the lesson plans of STEM education was significantly higher than before at the .05 level of statistics.

Discovery of Novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa.

This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against E. coli was maintained (IC50 > 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.

Beyond the Scope of Each Computational Chemistry

Due to recent advances in computational chemistry, not only computers and analysis programs in crystal structure analysis, but also TD-DFT calculations related to intramolecular electronic states and energies have been easily performed, and detailed discussions have become possible. On the other hand, how to discuss information such as intermolecular interactions, molecular assembly states, and packing, which is beyond the scope of application of each computational chemistry program and theory, is still a subject of research. Here, authors would like to consider what is possible and difficult using a program, for example, Hirshfeld surface analysis.

Exploring an Application of Principal Component Analysis to Laser-Induced Breakdown Spectroscopy of Stainless-Steel Standard Samples as a Research Project

Laser-induced breakdown spectroscopy (LIBS) and principal component analysis (PCA) are frequently used for analytical purposes in research and industry, but they seldom are part of the chemistry curriculum or laboratory exercises. This case study paper describes the combined application of LIBS and PCA during a research internship for an undergraduate student. The instructional method applied was based on a one-on-one mentorship, in which case the learner was engaged in a research work. The learning activities included theoretical introductions to the LIBS and PCA methods, numerical simulation, experiments, and data analysis. The study covered three main topics: analysis of LIBS spectra, application of PCA for clustering, and use of PCA for experimental design. The realization of the study was instructive for all parties involved: from the mentorship point of view, it is concluded that the topics can be covered during an internship or developed into a one semester long research-based module of a chemistry program or a final year project. The student, on the other hand, developed profound technical skills in performing experiments and using PCA software for data analysis.

Software for the frontiers of quantum chemistry: An overview of developments in the Q-Chem 5 package.

This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange-correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear-electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an "open teamware" model and an increasingly modular design.

Identification of unprecedented ATP-competitive choline kinase inhibitors

In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.

THỰC TRẠNG SỬ DỤNG THÍ NGHIỆM NHẰM PHÁT TRIỂN NĂNG LỰC CHO HỌC SINH TRONG DẠY HỌC HÓA HỌC Ở TRƯỜNG TRUNG HỌC PHỔ THÔNG

Experiments holds an important part in teaching chemistry in high school. 2018 General Education Program of chemistry highlights practicality, helping student gaining ability to conduct experiments and apply chemistry knowledge. Thus, investigation on usage of chemistry experiments is extremely vital. Survey result is scientific basic to determine solution accordingly to develop qualification in teaching and studying chemistry. This writing introduces survey result in experiment application and orienting measures to use chemical experiments to develop students' capacity, meeting the requirements of the general education program 2018.