Статті в журналах: "Biophysical screening"

1

Genick, Christine Clougherty, Danielle Barlier, Dominique Monna, Reto Brunner, Céline Bé, Clemens Scheufler, and Johannes Ottl. "Applications of Biophysics in High-Throughput Screening Hit Validation." Journal of Biomolecular Screening 19, no. 5 (April 2, 2014): 707–14. http://dx.doi.org/10.1177/1087057114529462.

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For approximately a decade, biophysical methods have been used to validate positive hits selected from high-throughput screening (HTS) campaigns with the goal to verify binding interactions using label-free assays. By applying label-free readouts, screen artifacts created by compound interference and fluorescence are discovered, enabling further characterization of the hits for their target specificity and selectivity. The use of several biophysical methods to extract this type of high-content information is required to prevent the promotion of false positives to the next level of hit validation and to select the best candidates for further chemical optimization. The typical technologies applied in this arena include dynamic light scattering, turbidometry, resonance waveguide, surface plasmon resonance, differential scanning fluorimetry, mass spectrometry, and others. Each technology can provide different types of information to enable the characterization of the binding interaction. Thus, these technologies can be incorporated in a hit-validation strategy not only according to the profile of chemical matter that is desired by the medicinal chemists, but also in a manner that is in agreement with the target protein’s amenability to the screening format. Here, we present the results of screening strategies using biophysics with the objective to evaluate the approaches, discuss the advantages and challenges, and summarize the benefits in reference to lead discovery. In summary, the biophysics screens presented here demonstrated various hit rates from a list of ~2000 preselected, IC50-validated hits from HTS (an IC50 is the inhibitor concentration at which 50% inhibition of activity is observed). There are several lessons learned from these biophysical screens, which will be discussed in this article.

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Linke, Pawel, Kwame Amaning, Melanie Maschberger, Francois Vallee, Valerie Steier, Philipp Baaske, Stefan Duhr, Dennis Breitsprecher, and Alexey Rak. "An Automated Microscale Thermophoresis Screening Approach for Fragment-Based Lead Discovery." Journal of Biomolecular Screening 21, no. 4 (December 2, 2015): 414–21. http://dx.doi.org/10.1177/1087057115618347.

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Fragment-based lead discovery has proved to be an effective alternative to high-throughput screenings in identifying chemical matter that can be developed into robust lead compounds. The search for optimal combinations of biophysical techniques that can correctly and efficiently identify and quantify binding can be challenging due to the physicochemical properties of fragments. In order to minimize the time and costs of screening, optimal combinations of biophysical techniques with maximal information content, sensitivity, and robustness are needed. Here we describe an approach utilizing automated microscale thermophoresis (MST) affinity screening to identify fragments active against MEK1 kinase. MST identified multiple hits that were confirmed by X-ray crystallography but not detected by orthogonal methods. Furthermore, MST also provided information about ligand-induced aggregation and protein denaturation. The technique delivered a large number of binders while reducing experimentation time and sample consumption, demonstrating the potential of MST to execute and maximize the efficacy of fragment screening campaigns.

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3

Kamel, Hassan S., Ahmed M. Makhlouf, and Alaaeldin A. Youssef. "Simplified Biophysical Profile: An Antepartum Fetal Screening Test." Gynecologic and Obstetric Investigation 47, no. 4 (1999): 223–28. http://dx.doi.org/10.1159/000010110.

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4

Renaud, Jean-Paul, and Marc-André Delsuc. "Biophysical techniques for ligand screening and drug design." Current Opinion in Pharmacology 9, no. 5 (October 2009): 622–28. http://dx.doi.org/10.1016/j.coph.2009.06.008.

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Patil, Devashree N., Sushama A. Patil, Srinivas Sistla, and Jyoti P. Jadhav. "Comparative biophysical characterization: A screening tool for acetylcholinesterase inhibitors." PLOS ONE 14, no. 5 (May 31, 2019): e0215291. http://dx.doi.org/10.1371/journal.pone.0215291.

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Murphy, Samuel L., Anand Bhagwat, Shyrie Edmonson, Shangzhen Zhou, and Katherine A. High. "High-throughput Screening and Biophysical Interrogation of Hepatotropic AAV." Molecular Therapy 16, no. 12 (December 2008): 1960–67. http://dx.doi.org/10.1038/mt.2008.210.

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Huang, Renjie, Daniel M. Ayine-Tora, M. Nasri Muhammad Rosdi, Yu Li, Jóhannes Reynisson, and Ivanhoe K. H. Leung. "Virtual screening and biophysical studies lead to HSP90 inhibitors." Bioorganic & Medicinal Chemistry Letters 27, no. 2 (January 2017): 277–81. http://dx.doi.org/10.1016/j.bmcl.2016.11.059.

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Ghodsvali, Alireza, Vahid Farzaneh, Hamid Bakhshabadi, Zahra Zare, Zahra Karami, Mohsen Mokhtarian, and Isabel S. Carvalho. "Screening of the aerodynamic and biophysical properties of barley malt." International Agrophysics 30, no. 4 (October 1, 2016): 457–64. http://dx.doi.org/10.1515/intag-2016-0017.

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AbstractAn understanding of the aerodynamic and biophysical properties of barley malt is necessary for the appropriate design of equipment for the handling, shipping, dehydration, grading, sorting and warehousing of this strategic crop. Malting is a complex biotechnological process that includes steeping; germination and finally, the dehydration of cereal grains under controlled temperature and humidity conditions. In this investigation, the biophysical properties of barley malt were predicted using two models of artificial neural networks as well as response surface methodology. Stepping time and germination time were selected as the independent variables and 1 000 kernel weight, kernel density and terminal velocity were selected as the dependent variables (responses). The obtained outcomes showed that the artificial neural network model, with a logarithmic sigmoid activation function, presents more precise results than the response surface model in the prediction of the aerodynamic and biophysical properties of produced barley malt. This model presented the best result with 8 nodes in the hidden layer and significant correlation coefficient values of 0.783, 0.767 and 0.991 were obtained for responses one thousand kernel weight, kernel density, and terminal velocity, respectively. The outcomes indicated that this novel technique could be successfully applied in quantitative and qualitative monitoring within the malting process.

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9

AFZAL, AYSHA, and KHALIDA NASREEN. "BIOPHYSICAL SCORE." Professional Medical Journal 13, no. 03 (June 25, 2006): 362–69. http://dx.doi.org/10.29309/tpmj/2006.13.03.4983.

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A pregnancy is defined as high risk when there is a likelihood of anadverse outcome to the woman and or her baby that is greater than the incidence of that outcome in the generalpregnant population. Objectives: To determine the efficacy and predictive value of biophysical profile in detectingperinatal outcome. Design: Observational study. Setting: Obstetrics and Gynaecology department, PNS SHIFA KarachiPeriod: From February 2003 to October 2003. Patients and Methods: The study was carried on 100 randomlyselected high risk pregnant patients who reported to gynae OPD or were referred from different armed forces hospitalsfrom all over sindh . Manning’s biophysical profile excluding nonstress test and including only ultrasound basedparameters were employed for fetal screening ( BPS 8/8). These parameters include four variables i.e fetal breathingmovement, fetal tone, fetal movements, and amniotic fluid volume. Nonstress test and Doppler studies were used asbackup tests where biophysical profile was abnormal. All cases selected were admitted in the hospital and each hadan admission biophysical profile followed by subsequent monitoring. Parameters for abnormal perinatal outcome includefetal distress in labour, five minute apgar score less than 7/10, admission of newborn to intensive care unit and stillbirthor neonatal death. The result of last biophysical profile is compared with perinatal outcome. For statistical analysis thepredictive value, specificity and sensitivity are used to determine the ability of biophysical profile to predict an abnormalperinatal outcome. Results: Out of 100 cases 92 had a normal biophysical profile in the last scan of 8/8. 90 cases hada normal perinatal outcome with A/S > 7/10. In two cases A/S at 1 and 5 minute is < 7/10 with one baby shifted tonursery for delayed cry. 08 cases had an abnormal biophysical profile with scores of 4/8 and 2/8. There was one falsepositive who showed abnormal biophysical profile but baby was born with an A/S of 8/10 at 05 minutes. There was noneonatal death in this study group. The sensitivity of biophysical profile was 77.7%, specificity 98.90%. predictive valuefor a positive test was 87.5%, predictive value for a negative test was 97.8%. Conclusion: Biophysical profile is highlyaccurate and reliable test of diagnosing fetal status.

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10

Santoso, Aline T., Xiaoyan Deng, Jeong-Hyun Lee, Kerryn Matthews, Simon P. Duffy, Emel Islamzada, Sarah M. McFaul, Marie-Eve Myrand-Lapierre, and Hongshen Ma. "Microfluidic cell-phoresis enabling high-throughput analysis of red blood cell deformability and biophysical screening of antimalarial drugs." Lab on a Chip 15, no. 23 (2015): 4451–60. http://dx.doi.org/10.1039/c5lc00945f.

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11

Wax, Joseph R., Angelina Cartin, and Michael G. Pinette. "Biophysical and Biochemical Screening for the Risk of Preterm Labor." Clinics in Laboratory Medicine 30, no. 3 (September 2010): 693–707. http://dx.doi.org/10.1016/j.cll.2010.04.006.

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12

Wax, Joseph R., Angelina Cartin, and Michael G. Pinette. "Biophysical and Biochemical Screening for the Risk of Preterm Labor." Clinics in Laboratory Medicine 36, no. 2 (June 2016): 369–83. http://dx.doi.org/10.1016/j.cll.2016.01.019.

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13

Kutchukian, Peter S., Anne Mai Wassermann, Mika K. Lindvall, S. Kirk Wright, Johannes Ottl, Jaison Jacob, Clemens Scheufler, Andreas Marzinzik, Natasja Brooijmans, and Meir Glick. "Large Scale Meta-Analysis of Fragment-Based Screening Campaigns." Journal of Biomolecular Screening 20, no. 5 (December 30, 2014): 588–96. http://dx.doi.org/10.1177/1087057114565080.

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A first step in fragment-based drug discovery (FBDD) often entails a fragment-based screen (FBS) to identify fragment “hits.” However, the integration of conflicting results from orthogonal screens remains a challenge. Here we present a meta-analysis of 35 fragment-based campaigns at Novartis, which employed a generic 1400-fragment library against diverse target families using various biophysical and biochemical techniques. By statistically interrogating the multidimensional FBS data, we sought to investigate three questions: (1) What makes a fragment amenable for FBS? (2) How do hits from different fragment screening technologies and target classes compare with each other? (3) What is the best way to pair FBS assay technologies? In doing so, we identified substructures that were privileged for specific target classes, as well as fragments that were privileged for authentic activity against many targets. We also revealed some of the discrepancies between technologies. Finally, we uncovered a simple rule of thumb in screening strategy: when choosing two technologies for a campaign, pairing a biochemical and biophysical screen tends to yield the greatest coverage of authentic hits.

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14

Holdgate, Geoffrey, Kevin Embrey, Alexander Milbradt, and Gareth Davies. "Biophysical methods in early drug discovery." ADMET and DMPK 7, no. 4 (December 10, 2019): 222–41. http://dx.doi.org/10.5599/admet.733.

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Biophysical methods such as mass spectrometry, surface plasmon resonance, nuclear magnetic resonance, and both differential scanning isothermal titration calorimetry are now well established as key components of the early drug discovery process. These approaches are used successfully for a range of activities, including assay development, primary screening, hit confirmation and detailed mechanistic characterisation of compound binding. Matching the speed, sensitivity and information content of the various techniques to the generation of critical data and information required at each phase of the drug discovery process has been key. This review describes the framework by which these methods have been applied in the drug discovery process and provides case studies to exemplify the impact.

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15

Chan, Daniel Shiu-Hin, Andrew J. Whitehouse, Anthony G. Coyne, and Chris Abell. "Mass spectrometry for fragment screening." Essays in Biochemistry 61, no. 5 (October 6, 2017): 465–73. http://dx.doi.org/10.1042/ebc20170071.

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Fragment-based approaches in chemical biology and drug discovery have been widely adopted worldwide in both academia and industry. Fragment hits tend to interact weakly with their targets, necessitating the use of sensitive biophysical techniques to detect their binding. Common fragment screening techniques include differential scanning fluorimetry (DSF) and ligand-observed NMR. Validation and characterization of hits is usually performed using a combination of protein-observed NMR, isothermal titration calorimetry (ITC) and X-ray crystallography. In this context, MS is a relatively underutilized technique in fragment screening for drug discovery. MS-based techniques have the advantage of high sensitivity, low sample consumption and being label-free. This review highlights recent examples of the emerging use of MS-based techniques in fragment screening.

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16

Xavier, K. Asish, Paul S. Eder, and Tony Giordano. "RNA as a drug target: methods for biophysical characterization and screening." Trends in Biotechnology 18, no. 8 (August 2000): 349–56. http://dx.doi.org/10.1016/s0167-7799(00)01464-5.

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17

Woestenenk, Esmeralda A., Martin Hammarström, Torleif Härd, and Helena Berglund. "Screening methods to determine biophysical properties of proteins in structural genomics." Analytical Biochemistry 318, no. 1 (July 2003): 71–79. http://dx.doi.org/10.1016/s0003-2697(03)00162-3.

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18

Mashalidis, Ellene H., Paweł Śledź, Steffen Lang, and Chris Abell. "A three-stage biophysical screening cascade for fragment-based drug discovery." Nature Protocols 8, no. 11 (October 24, 2013): 2309–24. http://dx.doi.org/10.1038/nprot.2013.130.

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19

Ghodsvali, Alireza, Vahid Farzaneh, Hamid Bakhshabadi, Zahra Zare, Zahra Karami, Mohsen Mokhtarian, and Isabel S. Carvalho. "Erratum to: Screening of the aerodynamic and biophysical properties of barley malt." International Agrophysics 31, no. 3 (July 1, 2017): 453. http://dx.doi.org/10.1515/intag-2016-0068.

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20

Sofela, Samuel, Sarah Sahloul, and Yong-Ak Song. "Biophysical analysis of drug efficacy on C. elegans models for neurodegenerative and neuromuscular diseases." PLOS ONE 16, no. 6 (June 11, 2021): e0246496. http://dx.doi.org/10.1371/journal.pone.0246496.

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Caenorhabditis elegans has emerged as a powerful model organism for drug screening due to its cellular simplicity, genetic amenability and homology to humans combined with its small size and low cost. Currently, high-throughput drug screening assays are mostly based on image-based phenotyping with the focus on morphological-descriptive traits not exploiting key locomotory parameters of this multicellular model with muscles such as its thrashing force, a critical biophysical parameter when screening drugs for muscle-related diseases. In this study, we demonstrated the use of a micropillar-based force assay chip in combination with a fluorescence assay to evaluate the efficacy of various drugs currently used in treatment of neurodegenerative and neuromuscular diseases. Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson’s Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model. These results underline the potential of our force assay chip in screening of potential drug candidates for the treatment of neurodegenerative and neuromuscular diseases when combined with a fluorescence assay in a two-dimensional analysis approach.

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Balboni, Beatrice, Shailesh Kumar Tripathi, Marina Veronesi, Debora Russo, Ilaria Penna, Barbara Giabbai, Tiziano Bandiera, Paola Storici, Stefania Girotto та Andrea Cavalli. "Identification of Novel GSK-3β Hits Using Competitive Biophysical Assays". International Journal of Molecular Sciences 23, № 7 (31 березня 2022): 3856. http://dx.doi.org/10.3390/ijms23073856.

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Glycogen synthase kinase 3 beta (GSK-3β) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer’s disease and cancer. Even though GSK-3β is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3β complete inhibition which translates into the impairment of the plethora of pathways GSK-3β is involved in. Starting from a 1D 19F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3β inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3β in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3β, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3β inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3β activity without leading to its complete inhibition.

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Scarpino, Bajusz, Proj, Gobec, Sosič, Gobec, Ferenczy, and Keserű. "Discovery of Immunoproteasome Inhibitors Using Large-Scale Covalent Virtual Screening." Molecules 24, no. 14 (July 16, 2019): 2590. http://dx.doi.org/10.3390/molecules24142590.

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Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the β5i subunit of the immunoproteasome. A hierarchical virtual screening cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory potency for two compounds. These results validate the computational protocol that allows the screening of large compound collections. One of the lead-like boronic acid derivatives identified as a covalent immunoproteasome inhibitor is a suitable starting point for chemical optimization.

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23

Price, Amanda J., Steven Howard, and Benjamin D. Cons. "Fragment-based drug discovery and its application to challenging drug targets." Essays in Biochemistry 61, no. 5 (November 8, 2017): 475–84. http://dx.doi.org/10.1042/ebc20170029.

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Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein–fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein–protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2.

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24

Park, Kijun, Yeontaek Lee, and Jungmok Seo. "Recent Advances in High-throughput Platforms with Engineered Biomaterial Microarrays for Screening of Cell and Tissue Behavior." Current Pharmaceutical Design 24, no. 45 (April 16, 2019): 5458–70. http://dx.doi.org/10.2174/1381612825666190207093438.

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In the last decades, bioengineers have developed myriad biomaterials for regenerative medicine. Development of screening techniques is essential for understanding complex behavior of cells in the biological microenvironments. Conventional approaches to the screening of cellular behavior in vitro have limitations in terms of accuracy, reusability, labor-intensive screening, and versatility. Thus, drug screening and toxicology test through in vitro screening platforms have been underwhelming. Recent advances in the high-throughput screening platforms somewhat overcome the limitations of in vitro screening platforms via repopulating human tissues’ biophysical and biomchemical microenvironments with the ability to continuous monitoring of miniaturized human tissue behavior. Herein, we review current trends in the screening platform in which a high-throughput system composed of engineered microarray devices is developed to investigate cell-biomaterial interaction. Furthermore, diverse methods to achieve continuous monitoring of cell behavior via developments of biosensor integrated high-throughput platforms, and future perspectives on high-throughput screening will be provided.

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25

Lakhno, I. V. "Modern possibilities of pre-eclampsia prediction and prevention." HEALTH OF WOMAN, no. 7(113) (September 30, 2016): 44–48. http://dx.doi.org/10.15574/hw.2016.113.4.

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The objective: study forecasting capabilities and PE drug prevention. Patients and methods. Totally 292 pregnant women and 154 pre-eclamptic patients were enrolled in the study. The traditional combination of biochemical and biophysical tests for the selection of high risk for PE patients were used (PI in the uterine arteries> 2.25; PAPP-A <0.69 MoM; b-hCG>3.0 MoM; AFP>2.5 MoM). Patients of group II were divided into subgroup II A and II subgroup B. This was done to evaluate the complex medical prophylaxis (CMP) of PE, which was administered in the II B subgroup. Results. The prospective study showed the following diagnostic value of a positive result in the screening for PE in subgroup II A. OR was 16.5. The sensitivity of this method was 87,1%, specificity – 71.0%, PPV – 75.0%, NPV – 84.6%, IA – 79.0%. The additional usage of the sympathovagal balance in the position on the right side and active orthostasis increased the predictive value of screening for PE in 4.5 times. The sensitivity of the method was 90.3% and specificity – 84.3%. PPV was 84.8%. NPV had a maximal value – 100.0%. IA – 92.3%. The proposed method of CMP decreased the odds of PE in 8.3 times. Conclusion. This study led to the development of pathogenetically reasonable screening protocol included biochemical and biophysical tests, as well as an effective method of PE prevention. Key words: preeclampsia, screening, drug prevention.

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Rainard, Julie M., George C. Pandarakalam, and Stuart P. McElroy. "Using Microscale Thermophoresis to Characterize Hits from High-Throughput Screening: A European Lead Factory Perspective." SLAS DISCOVERY: Advancing the Science of Drug Discovery 23, no. 3 (February 20, 2018): 225–41. http://dx.doi.org/10.1177/2472555217744728.

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High-throughput screening (HTS) is a proven method for discovering new lead matter for drug discovery and chemical biology. To maximize the likelihood of identifying genuine binders to a molecular target, and avoid wasting resources following up compounds with unproductive/nonspecific mechanisms of action, it is important to employ a range of assays during an HTS campaign that build confidence of target engagement for hit compounds. Biophysical methods that measure direct target/compound engagement have established themselves as key techniques in generating this confidence, and they are now integral to the latter stages of HTS triage at the European Lead Factory (ELF). One relatively new technique that the ELF is using is microscale thermophoresis (MST), which measures the differences in rate of movement through a temperature gradient that are caused when single molecular species form complexes. Here we provide an overview of the MST assay development workflow that the ELF employs and a perspective of our experience to date of using MST to triage the output of HTS campaigns and how it compares and contrasts with the use of other biophysical techniques.

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K., Hymavathi, Sandhya Rani Davuluru, Sameera Shaik, and Sahithi Kaviti. "Potential screening strategies for early prediction of pre-eclampsia." International Journal of Reproduction, Contraception, Obstetrics and Gynecology 10, no. 4 (March 24, 2021): 1436. http://dx.doi.org/10.18203/2320-1770.ijrcog20211116.

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Background: This study was conducted to evaluate the efficacy of different biochemical and biophysical markers in the early weeks of gestation as screening tools for early prediction of preeclampsia.Methods: This hospital-based prospective observational study conducted on 52 pregnant women, at less than 13 weeks of gestation were recruited. Maternal serum inhibin A and USG uterine artery PI levels were analyzed among the pregnant women who subsequently developed PE and compare with those who did not develop PE. Methods used for the detection of markers were: chemiluminescence immunoassay (CLIA) for serum inhibin A levels, and uterine artery Doppler velocimetry was done by PHILIPS HD11XE transabdominal ultrasound machine using a 4-6 MHz probe with the same sonographer.Results: The present study revealed a significant rise of inhibin A in preeclamptic women when compared to normotensive women (p<0.0001). The mean levels of 1st and 2nd trimester uterine artery PI significantly high in women who subsequently developed PE when compared to those who did not develop preeclampsia (p<0.0001). Study results showed a strong association between gestational age at delivery and neonatal outcome (neonatal birth weight and APGAR) with preeclampsia. The maternal serum inhibin A, and uterine artery PI found to have good sensitivity and specificity for early prediction of PE.Conclusions: Study concluded that the women who are prone to develop PE subsequently, had high levels of MAP, UAPI, inhibin A. In our setting, MAP, UAPI, inhibin A, appeared to be better screening modalities. Combination of the biochemical markers with the biophysical markers, demographic characteristics, and other novel markers will establish the effective screening models for early prediction of PE. Early identification of high-risk cases will offer an opportunity for prophylactic therapy, such as Low- dose Aspirin in selected groups of high-risk women screened in the first trimester, thus improving the maternal and perinatal outcome.

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Velazquez-Campoy, Adrián, Javier Sancho, Olga Abian, and Sonia Vega. "Biophysical Screening for Identifying Pharmacological Chaperones and Inhibitors Against Conformational and Infectious Diseases." Current Drug Targets 17, no. 13 (September 2, 2016): 1492–505. http://dx.doi.org/10.2174/1389450117666160201110449.

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Akolekar, Ranjit, Argyro Syngelaki, Leona Poon, David Wright, and Kypros H. Nicolaides. "Competing Risks Model in Early Screening for Preeclampsia by Biophysical and Biochemical Markers." Fetal Diagnosis and Therapy 33, no. 1 (August 16, 2012): 8–15. http://dx.doi.org/10.1159/000341264.

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Agamennone, Mariangela, Lucia Cesari, Daniela Lalli, Elisa Turlizzi, Rebecca Del Conte, Paola Turano, Stefano Mangani, and Alessandro Padova. "Fragmenting the S100B-p53 Interaction: Combined Virtual/Biophysical Screening Approaches to Identify Ligands." ChemMedChem 5, no. 3 (February 19, 2010): 428–35. http://dx.doi.org/10.1002/cmdc.200900393.

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Silvestre, H. L., T. L. Blundell, C. Abell, and A. Ciulli. "Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery." Proceedings of the National Academy of Sciences 110, no. 32 (July 19, 2013): 12984–89. http://dx.doi.org/10.1073/pnas.1304045110.

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32

Dalvit, Claudio. "NMR methods in fragment screening: theory and a comparison with other biophysical techniques." Drug Discovery Today 14, no. 21-22 (November 2009): 1051–57. http://dx.doi.org/10.1016/j.drudis.2009.07.013.

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Tian, Xinsheng, Annette E. Langkilde, Matthias Thorolfsson, Hanne B. Rasmussen, and Bente Vestergaard. "Small-Angle X-ray Scattering Screening Complements Conventional Biophysical Analysis: Comparative Structural and Biophysical Analysis of Monoclonal Antibodies IgG1, IgG2, and IgG4." Journal of Pharmaceutical Sciences 103, no. 6 (June 2014): 1701–10. http://dx.doi.org/10.1002/jps.23964.

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Hymavathi, Kaliki, Bhaavya Paturi, Duvvuru Akshitha, and K. Sravya. "Preeclampsia prediction –First trimester screening markers." Indian Journal of Obstetrics and Gynecology Research 8, no. 2 (June 15, 2021): 223–29. http://dx.doi.org/10.18231/j.ijogr.2021.046.

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Preeclampsia is a multi-system disorder manifested primarily by hypertension and proteinuria during second half of pregnancy. It is a major cause of maternal morbidity and mortality worldwide. Despite decades of research into the condition, the ability of clinicians to predict preeclampsia prior to the onset of symptoms has not improved significantly. In this review we will look at potential biomarkers for early prediction and diagnosis of preeclampsia. To evaluate the efficacy of different biochemical and biophysical markers in the early weeks of gestation as screening tools for early prediction of preeclampsia. This hospital-based prospective observational study conducted on 52 pregnant women, at less than 13 weeks of gestation were recruited. Maternal urine microalbumin, urinary albumin to creatinine ratio, and USG uterine artery PI levels were analyzed among the pregnant women who subsequently developed PE and compare with those who did not develop PE. Methods used for the detection of markers are: immunoturbidimetric method for urine albumin, modified kinetic Jaffe reaction without deproteinization for Urine creatinine and Uterine artery Doppler velocimetry was done by PHILIPS HD11XE transabdominal ultrasound machine using a 4-6 MHz probe with the same sonographer. In the present study, spot urine microalbumin and spot urine albumin to creatinine ratio (UACR) at 11-13 were significantly higher in women who developed PE subsequently when compared to nonpreeclamptic women.(P<0.0001). The mean levels of 1st and 2nd-trimester uterine artery PI significantly high in women who subsequently developed PE when compared to those who did not develop preeclampsia (P<0.0001). Study results showed a strong association between gestational age at delivery and neonatal outcome (neonatal birth weight and APGAR) with preeclampsia. The maternal urine microalbumin, albumin to creatinine ratio, and uterine artery PI found to have good sensitivity and specificity for early prediction of PE. Study concluded that the women who are prone to develop PE subsequently, had high levels of MAP, UAPI, microalbuminuria and urine albumin to creatinine ratio than the normotensive women. In our setting, MAP, UAPI, microalbuminuria, and UACR markers appeared to be better screening modalities. The combination of biochemical markers with the biophysical markers, demographic characteristics, and other novel markers will establish the effective screening models for early prediction of PE. Early identification of high-risk cases will offer an opportunity for prophylactic therapy, such as Low- dose Aspirin in selected groups of high-risk women screened in the first trimester, thus improving the maternal and perinatal outcome.

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Sun, Wei, Chwee Teck Lim, and Nicholas Agung Kurniawan. "Mechanistic adaptability of cancer cells strongly affects anti-migratory drug efficacy." Journal of The Royal Society Interface 11, no. 99 (October 6, 2014): 20140638. http://dx.doi.org/10.1098/rsif.2014.0638.

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Cancer metastasis involves the dissemination of cancer cells from the primary tumour site and is responsible for the majority of solid tumour-related mortality. Screening of anti-metastasis drugs often includes functional assays that examine cancer cell invasion inside a three-dimensional hydrogel that mimics the extracellular matrix (ECM). Here, we built a mechanically tuneable collagen hydrogel model to recapitulate cancer spreading into heterogeneous tumour stroma and monitored the three-dimensional invasion of highly malignant breast cancer cells, MDA-MB-231. Migration assays were carried out in the presence and the absence of drugs affecting four typical molecular mechanisms involved in cell migration, as well as under five ECMs with different biophysical properties. Strikingly, the effects of the drugs were observed to vary strongly with matrix mechanics and microarchitecture, despite the little dependence of the inherent cancer cell migration on the ECM condition. Specifically, cytoskeletal contractility-targeting drugs reduced migration speed in sparse gels, whereas migration in dense gels was retarded effectively by inhibiting proteolysis. The results corroborate the ability of cancer cells to switch their multiple invasion mechanisms depending on ECM condition, thus suggesting the importance of factoring in the biophysical properties of the ECM in anti-metastasis drug screenings.

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Kraft, Lucas, Louise Serpell, and John Atack. "A Biophysical Approach to the Identification of Novel ApoE Chemical Probes." Biomolecules 9, no. 2 (January 29, 2019): 48. http://dx.doi.org/10.3390/biom9020048.

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Alzheimer’s disease (AD) is the most common type of dementia and, after age, the greatest risk factor for developing AD is the allelic variation of apolipoprotein E (ApoE), with homozygote carriers of the ApoE4 allele having an up to 12-fold greater risk of developing AD than noncarriers. Apolipoprotein E exists as three isoforms that differ in only two amino acid sites, ApoE2 (Cys112/Cys158), ApoE3 (Cys112/Arg158), and ApoE4 (Arg112/Arg158). These amino acid substitutions are assumed to alter ApoE structure and function, and be responsible for the detrimental effects of ApoE4 via a mechanism that remains unclear. The hypothesis that a structural difference between ApoE4 and ApoE3 (and ApoE2) is the cause of the ApoE4-associated increased risk for AD forms the basis of a therapeutic approach to modulate ApoE4 structure, and we were therefore interested in screening to identify new chemical probes for ApoE4. In this regard, a high-yield protocol was developed for the expression and purification of recombinant full-length ApoE, and three diverse biophysical screening assays were established and characterized; an optical label-free assay (Corning Epic) for hit identification and microscale thermophoresis (MST) and isothermal titration calorimetry (ITC) as orthogonal assays for hit confirmation. The 707 compounds in the National Institute of Health clinical collection were screened for binding to ApoE4, from which six confirmed hits, as well as one analogue, were identified. Although the compounds did not differentiate between ApoE isoforms, these data nevertheless demonstrate the feasibility of using a biophysical approach to identifying compounds that bind to ApoE and that, with further optimization, might differentiate between isoforms to produce a molecule that selectively alters the function of ApoE4.

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37

Maurer, Christine K., Martina Fruth, Martin Empting, Olga Avrutina, Jörn Hoßmann, Suvd Nadmid, Jan Gorges, et al. "Discovery of the first small-molecule CsrA–RNA interaction inhibitors using biophysical screening technologies." Future Medicinal Chemistry 8, no. 9 (June 2016): 931–47. http://dx.doi.org/10.4155/fmc-2016-0033.

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Du, Jintong, Lulu Liu, Bo Liu, Jing Yang, Xuben Hou, Jinming Yu, and Hao Fang. "Structure-based virtual screening, biological evaluation and biophysical study of novel Mcl-1 inhibitors." Future Medicinal Chemistry 12, no. 14 (July 2020): 1293–304. http://dx.doi.org/10.4155/fmc-2020-0114.

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Aim: Targeting the protein–protein interactions (PPIs) associated with Mcl-1 has become a promising therapeutic approach for cancer. Herein, we reported the discovery of novel Mcl-1 inhibitors using an integrated computational approach. Results: Among 30 virtual screening hits, five compounds show inhibitory activities against Mcl-1. The most potent inhibitors M02 ( K i = 5.4 μM) and M08 ( Ki = 0.53 μM) exhibit good selectivity against Bcl-2 and Bcl-xL. Compound M08 exhibits anti-proliferation activity and induces caspase-3 activation in Jurkat cancer cells. Moreover, 1H⁄15N HSQC NMR experiments suggested that compound M08 likely binds in the P2 pocket of Mcl-1 and engages R263 in a salt bridge. Conclusion: Our study provides a good starting point for future discovery of more potent Mcl-1 selective inhibitors.

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39

Tserensambuu, Urjindelger, Ariunbold Chuluun-Erdene, Munkhtsetseg Janlav, and Erkhembaatar Tudevdorj. "The Use of Biochemical and Biophysical Markers in Early Screening for Preeclampsia in Mongolia." Medical Sciences 6, no. 3 (July 20, 2018): 57. http://dx.doi.org/10.3390/medsci6030057.

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Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality, particularly in developing countries. In Mongolia, preeclampsia and eclampsia have occurred among pregnancy complications at a rate of 25% in recent years. Recent studies in the literature have screened for preeclampsia by combining maternal factors with biomarkers. This study was conducted using prospective cohort research including 393 singleton pregnancies at 11–13+6 weeks. Maternal plasmas pregnancy-associated plasma protein-A (PAPP-A) and maternal serum placental growth factor (PlGF) were measured using Perkin Elmer time-resolved fluoroimmunoassay (DELFIA) kits, and the measurement of mean arterial pressure (MAP) was performed by automated devices and the uterine artery pulsatility index was measured by Doppler ultrasound. In the study population, there were 16.7% showing complicated preeclampsia. The receiver-operating characteristics (ROC) curve analysis showed a sensitivity of 71.21%, and a specificity of 75.54% when the mean arterial pressure cut-off was 89.5 mm; while a sensitivity of 33.36% and specificity of 77.68% were observed when the uterine artery mean pulsatility index (mPI) cut-off was 2.34; a sensitivity of 79.66% and specificity of 44.04% were observed when the PAPP-A cut-off was 529.1 mU/L; and a sensitivity of 74.58% and specificity of 46.6% were observed when the PlGF cut-off was 39.87 pg/mL. The detection rates following the combination of markers with the maternal history were as follows: 62.7% with mean arterial pressure, 69.5–82.9% with two markers 86.5% with three markers and 91.4% with four markers. In conclusion, the mean arterial pressure was highly sensitive and demonstrated its easy usage and cost-effectiveness as a predictive marker for the early screening of preeclampsia from other biomarkers.

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Caliari, Steven R., Emily A. Gonnerman, William K. Grier, Daniel W. Weisgerber, Jessica M. Banks, Aurora J. Alsop, Jae-Sung Lee, Ryan C. Bailey, and Brendan A. C. Harley. "Collagen Scaffold Arrays for Combinatorial Screening of Biophysical and Biochemical Regulators of Cell Behavior." Advanced Healthcare Materials 4, no. 1 (July 2, 2014): 58–64. http://dx.doi.org/10.1002/adhm.201400252.

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41

Rocca, Roberta, Federica Moraca, Giosuè Costa, Matteo Nadai, Matteo Scalabrin, Carmine Talarico, Simona Distinto, et al. "Identification of G-quadruplex DNA/RNA binders: Structure-based virtual screening and biophysical characterization." Biochimica et Biophysica Acta (BBA) - General Subjects 1861, no. 5 (May 2017): 1329–40. http://dx.doi.org/10.1016/j.bbagen.2016.12.023.

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42

Schiebel, Johannes, Nedyalka Radeva, Helene Köster, Alexander Metz, Timo Krotzky, Maren Kuhnert, Wibke E. Diederich, et al. "One Question, Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists." ChemMedChem 10, no. 9 (August 10, 2015): 1511–21. http://dx.doi.org/10.1002/cmdc.201500267.

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43

Ebert, Andrea, and Kai-Uwe Goss. "Screening of 6000 Compounds for Uncoupling Activity: A Comparison Between a Mechanistic Biophysical Model and the Structural Alert Profiler Mitotox." Toxicological Sciences 185, no. 2 (November 22, 2021): 208–19. http://dx.doi.org/10.1093/toxsci/kfab139.

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Abstract Protonophoric uncoupling of phosphorylation is an important factor when assessing chemicals for their toxicity, and has recently moved into focus in pharmaceutical research with respect to the treatment of diseases such as cancer, diabetes, or obesity. Reliably identifying uncoupling activity is thus a valuable goal. To that end, we screened more than 6000 anionic compounds for in vitro uncoupling activity, using a biophysical model based on ab initio COSMO-RS input parameters with the molecular structure as the only external input. We combined these results with a model for baseline toxicity (narcosis). Our model identified more than 1250 possible uncouplers in the screening dataset, and identified possible new uncoupler classes such as thiophosphoric acids. When tested against 423 known uncouplers and 612 known inactive compounds in the dataset, the model reached a sensitivity of 83% and a specificity of 96%. In a direct comparison, it showed a similar specificity than the structural alert profiler Mitotox (97%), but much higher sensitivity than Mitotox (47%). The biophysical model thus allows for a more accurate screening for uncoupling activity than existing structural alert profilers. We propose to use our model as a complementary tool to screen large datasets for protonophoric uncoupling activity in drug development and toxicity assessment.

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44

Videira, Natália Bernardi, Fernanda Aparecida Heleno Batista, Artur Torres Cordeiro, and Ana Carolina Migliorini Figueira. "Cellular and Biophysical Pipeline for the Screening of Peroxisome Proliferator-Activated Receptor Beta/Delta Agonists: Avoiding False Positives." PPAR Research 2018 (2018): 1–14. http://dx.doi.org/10.1155/2018/3681590.

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Peroxisome proliferator-activated receptor beta/delta (PPARß/δ) is considered a therapeutic target for metabolic disorders, cancer, and cardiovascular diseases. Here, we developed one pipeline for the screening of PPARß/δ agonists, which reduces the cost, time, and false-positive hits. The first step is an optimized 3-day long cellular transactivation assay based on reporter-gene technology, which is supported by automated liquid-handlers. This primary screening is followed by a confirmatory transactivation assay and by two biophysical validation methods (thermal shift assay (TSA) and (ANS) fluorescence quenching), which allow the calculation of the affinity constant, giving more information about the selected hits. All of the assays were validated using well-known commercial agonists providing trustworthy data. Furthermore, to validate and test this pipeline, we screened a natural extract library (560 extracts), and we found one plant extract that might be interesting for PPARß/δ modulation. In conclusion, our results suggested that we developed a cheaper and more robust pipeline that goes beyond the single activation screening, as it also evaluates PPARß/δ tertiary structure stabilization and the ligand affinity constant, selecting only molecules that directly bind to the receptor. Moreover, this approach might improve the effectiveness of the screening for agonists that target PPARß/δ for drug development.

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Ahmed, Alveena, Stephen Boulton, Hongzhao Shao, Madoka Akimoto, Amarnath Natarajan, Xiaodong Cheng, and Giuseppe Melacini. "Recent Advances in EPAC-Targeted Therapies: A Biophysical Perspective." Cells 8, no. 11 (November 19, 2019): 1462. http://dx.doi.org/10.3390/cells8111462.

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The universal second messenger cAMP regulates diverse intracellular processes by interacting with ubiquitously expressed proteins, such as Protein Kinase A (PKA) and the Exchange Protein directly Activated by cAMP (EPAC). EPAC is implicated in multiple pathologies, thus several EPAC-specific inhibitors have been identified in recent years. However, the mechanisms and molecular interactions underlying the EPAC inhibition elicited by such compounds are still poorly understood. Additionally, being hydrophobic low molecular weight species, EPAC-specific inhibitors are prone to forming colloidal aggregates, which result in non-specific aggregation-based inhibition (ABI) in aqueous systems. Here, we review from a biophysical perspective the molecular basis of the specific and non-specific interactions of two EPAC antagonists—CE3F4R, a non-competitive inhibitor, and ESI-09, a competitive inhibitor of EPAC. Additionally, we discuss the value of common ABI attenuators (e.g., TX and HSA) to reduce false positives at the expense of introducing false negatives when screening aggregation-prone compounds. We hope this review provides the EPAC community effective criteria to evaluate similar compounds, aiding in the optimization of existing drug leads, and informing the development of the next generation of EPAC-specific inhibitors.

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Nash, Michael A. "Single-molecule and Single-cell Approaches in Molecular Bioengineering." CHIMIA International Journal for Chemistry 74, no. 9 (September 30, 2020): 704–9. http://dx.doi.org/10.2533/chimia.2020.704.

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Protein sequences inhabit a discrete set in macromolecular space with incredible capacity to treat human disease. Despite our ability to program and manipulate protein sequences, the vast majority of protein development efforts are still done heuristically without a unified set of guiding principles. This article highlights work in understanding biophysical stability and function of proteins, developing new biophysical measurement tools and building high-throughput screening platforms to explore functional protein sequences. We highlight two primary areas. First, molecular biomechanics is a subfield concerned with the response of proteins to mechanical forces, and how we can leverage mechanical force to control protein function. The second subfield investigates the use of polymers and hydrogels in protein engineering and directed evolution in pursuit of new molecular systems with therapeutic applications. These two subdisciplines complement each other by shedding light onto sequence and structural features that can be used to impart stability into therapeutic proteins.

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Molinski, Steven V., Zoltán Bozóky, Surtaj H. Iram, and Saumel Ahmadi. "Biophysical Approaches Facilitate Computational Drug Discovery for ATP-Binding Cassette Proteins." International Journal of Medicinal Chemistry 2017 (March 19, 2017): 1–9. http://dx.doi.org/10.1155/2017/1529402.

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Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank. However, recent improvements to biophysical techniques (e.g., cryo-electron microscopy) have allowed for previously “hard-to-study” ABC proteins to be characterized at high resolution, providing insight into molecular mechanisms-of-action as well as revealing novel druggable sites for therapy design. These new advances provide ample opportunity for computational methods (e.g., virtual screening, molecular dynamics simulations, and structure-based drug design) to catalyze the discovery of novel small molecule therapeutics that can be easily translated from computer to bench and subsequently to the patient’s bedside. In this review, we explore the utility of recent advances in biophysical methods coupled with well-established in silico techniques towards drug development for diseases caused by dysfunctional ABC proteins.

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Jeridi, Semir, Alexey Rak, Amit Gupta, and Pierre Soule. "Fast Mek1 Hit Identification with TRIC Technology Correlates Well with Other Biophysical Methods." SLAS DISCOVERY: Advancing the Science of Drug Discovery 26, no. 8 (July 8, 2021): 1014–19. http://dx.doi.org/10.1177/24725552211026267.

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The variety and complexity of drug targets are expanding rapidly. At the same time, there is significant interest in exploring a larger chemical space to identify new candidates. Fragment-based screening (FBS) has emerged as a popular alternative to traditional high-throughput screening campaigns to identify such drug candidates. FBS identifies hit fragments that exhibit weak interactions with the target of interest, thereby enabling the rational design of small-molecule compounds from the identified hit fragments, which serve as building blocks. This strategy reduces the number of molecules to screen while also allowing the exploration of a greater chemical space. Here we use temperature-related intensity change (TRIC) technology to perform FBS against the target MAPK/ERK kinase-1 (Mek1). TRIC describes the change in fluorescence intensity of a fluorescently labeled molecule upon a change in temperature. This intensity variation is dependent on the physicochemical environment in the vicinity of the dye and strongly affected by binding events. Thus, the detection of binding events is independent of mass, making TRIC an ideal tool for FBS. Using only 150 pmol of labeled Mek1, the authors screened 193 fragments from a prescreened library in less than 1 h of measurement time, leading to 66 hits. Among those hits, they identified more than 80% of the published top hits found using orthogonal techniques. Furthermore, TRIC allowed the identification of fragments that were of poor solubility but could be mistaken as false-positive hits in other methods.

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Sikora, Mateusz, Utz H. Ermel, Anna Seybold, Michael Kunz, Giulia Calloni, Julian Reitz, R. Martin Vabulas, Gerhard Hummer, and Achilleas S. Frangakis. "Desmosome architecture derived from molecular dynamics simulations and cryo-electron tomography." Proceedings of the National Academy of Sciences 117, no. 44 (October 16, 2020): 27132–40. http://dx.doi.org/10.1073/pnas.2004563117.

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Desmosomes are cell–cell junctions that link tissue cells experiencing intense mechanical stress. Although the structure of the desmosomal cadherins is known, the desmosome architecture—which is essential for mediating numerous functions—remains elusive. Here, we recorded cryo-electron tomograms (cryo-ET) in which individual cadherins can be discerned; they appear variable in shape, spacing, and tilt with respect to the membrane. The resulting sub-tomogram average reaches a resolution of ∼26 Å, limited by the inherent flexibility of desmosomes. To address this challenge typical of dynamic biological assemblies, we combine sub-tomogram averaging with atomistic molecular dynamics (MD) simulations. We generate models of possible cadherin arrangements and perform an in silico screening according to biophysical and structural properties extracted from MD simulation trajectories. We find a truss-like arrangement of cadherins that resembles the characteristic footprint seen in the electron micrograph. The resulting model of the desmosomal architecture explains their unique biophysical properties and strength.

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Conole, Daniel, Samuel H. Myers, Filipa Mota, Adrian J. Hobbs, and David L. Selwood. "Biophysical screening methods for extracellular domain peptide receptors, application to natriuretic peptide receptor C ligands." Chemical Biology & Drug Design 93, no. 6 (October 10, 2018): 1011–20. http://dx.doi.org/10.1111/cbdd.13395.

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