10 películas para entender la evolución del periodismo en el séptimo arte.

Se trata de un análisis de 10 películas de periodismo y cómo cada una de ellas retrata de manera diferente la misma profesión, el periodismo. Desde el magnate de los medios de comunicación hasta el grupo de periodistas que destapa un escándalo de proporciones bíblicas, pasando por un dibujante solitario que se obsesiona con un asesino en serie o un fotógrafo de guerra en un conflicto que, si bien es ficticio, podría darse en cualquier momento de nuestra sociedad. La humanidad ha evolucionado y, con ella, nuestra capacidad para plasmar la realidad en imágenes en movimiento. Con este trabajo se pretende analizar y explicar cómo la gran pantalla capta en cada momento de la historia la profesión de los periodistas, cómo cambia esa visión dependiendo del momento histórico en el que se realizaron o en la mirada de cada uno de sus autores.This is an analysis of 10 journalism films and how each one portrays the same profession, journalism, in a different way. From a media tycoon to a group of journalists who uncover a scandal of biblical proportions, to a solitary cartoonist who becomes obsessed with a serial killer, to a war photographer in a conflict that, while fictional, could occur at any time in our society. Humanity has evolved, and, with it, our ability to capture reality in moving images. This work aims to analyze and explain how the big screen captures the profession of journalism at every moment in history, how that vision changes depending on the historical moment in which the films were made or the perspective of each of their creators

Freezing the Dynamic Gap for Selectivity: Motion‐Based Design of Inhibitors of the Shikimate Kinase Enzyme

This is the peer-reviewed version of the following article: Prado, V., Lence, E., Thompson, P., Hawkins, A., & González-Bello, C. (2016). Freezing the Dynamic Gap for Selectivity: Motion-Based Design of Inhibitors of the Shikimate Kinase Enzyme. Chemistry - A European Journal, 22(50), 17988-18000, which has been published in final form at https://doi.org/10.1002/chem.201602923. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingShikimate kinase (SK), the fifth enzyme of the aromatic amino acid biosynthesis, is a recognized target for antibiotic drug discovery. The potential of the distinct dynamic apolar gap, which isolates the natural substrate from the solvent environment for catalysis, and the motion of Mycobacterium tuberculosis and Helicobacter pylori SK enzymes, which was observed by molecular dynamics simulations, was explored for inhibition selectivity. The results of the biochemical and computational studies reveal that the incorporation of bulky groups at position C5 of 5‐aminoshikimic acid and the natural substrate enhances the selectivity for the H. pylori enzyme due to key motion differences in the shikimic acid binding domain (mainly helix α5). These studies show that the less‐exploited motion‐based design approach not only is an alternative strategy for the development of competitive inhibitors, but could also be a way to achieve selectivity against a particular enzyme among its homologuesSpanish Ministry of Economy and Competiveness. Grant Number: SAF2013-42899-R Xunta de Galicia. Grant Number: GRC2013-041 European Regional Development Fund (ERDF) Spanish Ministry of Economy and Competiveness Xunta de GaliciaS

Singlet oxygen and radical-mediated mechanisms in the oxidative cellular damage photosensitized by the protease inhibitor simeprevir

[EN] Hepatitis C, a liver inflammation caused by the hepatitis C virus (HCV), is treated with antiviral drugs. In this context, simeprevir (SIM) is an NS3/4A protease inhibitor used in HCV genotypes 1 and 4. It is orally admin-istered and achieves high virological cure rates. Among adverse reactions associated with SIM treatment, photosensitivity reactions have been reported. In the present work, it is clearly shown that SIM is markedly phototoxic, according to the in vitro NRU assay using BALB/c 3T3 mouse fibroblast. This result sheds light on the nature of the photosensitivity reactions induced by SIM in HCV patients, suggesting that porphyrin elevation in patients treated with SIM may not be the only mechanism responsible for SIM-associated photosensitivity. Moreover, lipid photoperoxidation and protein photooxidation assays, using human skin fibroblasts (FSK) and human serum albumin (HSA), respectively, reveal the capability of this drug to promote photodamage to cellular membranes. Also, DNA photo lesions induced by SIM are noticed through comet assay in FSK cells. Photo-chemical and photobiological studies on the mechanism of SIM-mediated photodamage to biomolecules indicate that the key transient species generated upon SIM irradiation is the triplet excited state. This species is efficiently quenched by oxygen giving rise to singlet oxygen, which is responsible for the oxidation of lipids and DNA (Type II mechanism). In the presence of HSA, the photobehavior is dominated by binding to site 3 of the protein, to give a stable SIM@HSA complex. Inside the complex, quenching of the triplet excited state is less efficient, which results in a longer triplet lifetime and in a decreased singlet oxygen formation. Hence, SIM-mediated photoox-idation of the protein is better explained through a radical (Type I) mechanism.Financial support from the Spanish Ministry of Science and Innovation [PID2020-115010RB-I00/AEI/10.13039/501100011033 (I.A), PID2019-105512RB-I00/AEI/10.13039/501100011033 (CG-B) and FPU predoctoral fellowship for M. El O.], Axencia Galega de Innovacion (2020-PG067, CG-B), the Xunta de Galicia [ED431C 2021/29 and the Centro singular de investigacion de Galicia accreditation 2019-2022 (ED431G 2019/03),], and the European Regional Development Fund (ERDF) is gratefully acknowledged. All authors are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer.García-Laínez, G.; El Ouardi, M.; Moreno, A.; Lence, E.; González-Bello, C.; Miranda, MÁ.; Andreu, I. (2023). Singlet oxygen and radical-mediated mechanisms in the oxidative cellular damage photosensitized by the protease inhibitor simeprevir. Free Radical Biology and Medicine. 194:42-51. https://doi.org/10.1016/j.freeradbiomed.2022.11.006425119

Synthesis of rigidified shikimic acid derivatives by ring-closing metathesis to imprint inhibitor efficacy against shikimate kinase enzyme

Diverse rigidified shikimic acids derivatives, which are stable mimetics of the high-energy conformation of shikimic acid, have been synthesized to enhance inhibitor efficacy against shikimate kinase enzyme (SK), an attractive target for antibiotic drug discovery. The synthesis of the reported conformationally restricted shikimic acid derivatives was carried out by ring-closing metathesis of allyloxy vinyl derivatives as the key step. The rigidification of the ligand conformation was used to maximize the effectiveness of the substituents introduced in the ether carbon bridge of the scaffold by pre-orienting their interaction with key residues and enzyme domains that are essential for catalysis and enzyme motion. Molecular Dynamics simulation studies on the enzyme/ligand complexes revealed marked differences in the positioning of the ligand substituent in the active site of the two enzymes studied (SK from Mycobacterium tuberculosis and Helicobacter pylori) and this explains their greater efficacy against one of the enzymes. This enhancement is due to the distinct induced-fit motion of the two homologous enzymes. A 20-fold improvement against the H. pylori enzyme was achieved by the introduction of a CH2OEt group in the rigid ether bridge of the reported shikimic acid analogsFinancial support from the Spanish Ministry of Economy and Competiveness (SAF2016-75638-R), the Xunta de Galicia [Centro singular de investigación de Galicia accreditation 2016–2019 (ED431G/09) and ED431B 2018/04], and the European Union (European Regional Development Fund –ERDF) is gratefully acknowledged. MP and EL thank the Xunta de Galicia for their respective predoctoral and postdoctoral fellowshipsS

Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting

[EN] Latent electrophiles are nowadays very attractive chemical entities for drug discovery, as they are unreactive unless activated upon binding with the specific target. In this work, the utility of 4-trifluoromethyl phenols as precursors of latent electrophiles, quinone methides (QM), for lysine-targeting is demonstrated. These Michael acceptors were photogenerated for specific covalent modification of lysine residues using human serum albumin (HSA) as a model target. The reactive QM-type intermediates I or II, generated upon irradiation of 4-trifluoromethyl-1-naphthol (1)@HSA or 4-(4-trifluorometylphenyl)phenol (2)@HSA complexes, exhibited chemoselective reactivity toward lysine residues leading to amide adducts, which was confirmed by proteomic analysis. For ligand 1, the covalent modification of residues Lys106 and Lys414 (located in subdomains IA and IIIA, respectively) was observed, whereas for ligand 2, the modification of Lys195 (in subdomain IIA) took place. Docking and molecular dynamics simulation studies provided an insight into the molecular basis of the selectivity of 1 and 2 for these HSA subdomains and the covalent modification mechanism. These studies open the opportunity of performing protein silencing by generating reactive ligands under very mild conditions (irradiation) for specific covalent modification of hidden lysine residues.Financial support from the Spanish Ministry of Economy and Competiveness [CTQ2016-78875-P, SAF2016-75638-R and BES-2014-069404 (predoctoral fellowship to O.M.-M.)], the Generalitat Valenciana (PROMETEO/2017/075), the Community of Madrid (2016-T1/AMB-1275), the Xunta de Galicia (Centro Singular de Investigacion de Galicia accreditation 2016-2019, ED431G/09 and postdoctoral fellowship to E.L.), and the European Union (European Regional Development Fund, ERDF) is gratefully acknowledged. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer.Pérez Ruiz, R.; Molins-Molina, O.; Lence, E.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2018). Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting. The Journal of Organic Chemistry. 83(21):13019-13029. https://doi.org/10.1021/acs.joc.8b01559S1301913029832

A new species of Veronica L. (Scrophulariaceae) in the Cantabrian Range (Spain)

[EN] A new species of Veronica vadiniense in section Veronica is described from material from the Cantabrian Range, in the north-east of the province of León (north-west Spain). Several morphological characters related to stems, leaves, racemes, flowers and capsules are given, and also those related to the indumentum of different parts of the plant, especially calyx lobes and capsule. Indications about distribution and habitat with reference to bioclimatic, biogeographical and phytosociological aspects are provided. Diagnostic features are also given to enable comparison with the most similar species, Veronica officinalis and V. allionii, particularly in the indumentum and consistency of leaves, and in the indumentum and shape of the capsule.S

Mechanistic insight into the reaction catalysed by bacterial type II dehydroquinases

DHQ2 (type II dehydroquinase), which is an essential enzyme in Helicobacter pylori and Mycobacterium tuberculosis and does not have any counterpart in humans, is recognized to be an attractive target for the development of new antibacterial agents. Computational and biochemical studies that help understand in atomic detail the catalytic mechanism of these bacterial enzymes are reported in the present paper. A previously unknown key role of certain conserved residues of these enzymes, as well as the structural changes responsible for triggering the release of the product from the active site, were identified. Asp89*/Asp88* from a neighbouring enzyme subunit proved to be the residue responsible for the deprotonation of the essential tyrosine to afford the catalytic tyrosinate, which triggers the enzymatic process. The essentiality of this residue is supported by results from site-directed mutagenesis. For H. pylori DHQ2, this reaction takes place through the assistance of a water molecule, whereas for M. tuberculosis DHQ2, the tyrosine is directly deprotonated by the aspartate residue. The participation of a water molecule in this deprotonation reaction is supported by solvent isotope effects and proton inventory studies. MD simulation studies provide details of the required motions for the catalytic turnover, which provides a complete overview of the catalytic cycle. The product is expelled from the active site by the essential arginine residue and after a large conformational change of a loop containing two conserved arginine residues (Arg109/Arg108 and Arg113/Arg112), which reveals a previously unknown key role for these residues. The present study highlights the key role of the aspartate residue whose blockage could be useful in the rational design of inhibitors and the mechanistic differences between both enzymesFinancial support from the Comunidad de Madrid (S2010-BMD-2457 to F.G.), Xunta de Galicia (10PXIB2200122PR and GRC2010/12 to C.G.-B.) and the Spanish Ministry of Science and Innovation (SAF2009-13914-C02-02 to F.G. and SAF2010-15076 to C.G.-B.) is 5076 to CGB and BFU2008-01588/BMC to MJvR) is gratefully acknowledged. C.C. and A.P. thank the Spanish Ministry of Science and Innovation for their respective FPU fellowshipsS

Study of the Phosphoryl‐Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy

This is the peer-reviewed version of the following article: Prado, V., Lence, E., Vallejo, J., Beceiro, A., Thompson, P., Hawkins, A., & González-Bello, C. (2016). Study of the Phosphoryl-Transfer Mechanism of Shikimate Kinase by NMR Spectroscopy. Chemistry - A European Journal, 22(8), 2758-2768, which has been published in final form at https://doi.org/10.1002/chem.201504438. This article may be used for non-commercial purposes in accordance with Wiley-VCH Terms and Conditions for Self-ArchivingThe phosphoryl‐transfer mechanism of shikimate kinase from Mycobacterium tuberculosis and Helicobacter pylori, which is an attractive target for antibiotic drug discovery, has been studied by 1D 1H and 31P NMR spectroscopy. Metaphosphoric acid proved to be a good mimetic of the metaphosphate intermediate and facilitated the ready and rapid evaluation by NMR spectroscopic analysis of a dissociative mechanism. The required closed form of the active site for catalysis was achieved by the use of ADP (product) or two synthetic ADP analogues (AMPNP, AMPCP). Molecular dynamics simulation studies reported here also revealed that the essential arginine (Arg116/Arg117 in H. pylori and M. tuberculosis, respectively), which activates the γ‐phosphate group of ATP for catalysis and triggers the release of the product for turnover, would also be involved in the stabilisation of the metaphosphate intermediate during catalysis. We believe that the studies reported here will be helpful for future structure‐based design of inhibitors of this attractive target. The approach is also expected be useful for studies on the possible dissociative mechanism of other kinase enzymesSpanish Ministry of Economy and Competiveness. Grant Number: SAF2013-42899-R Xunta de Galicia. Grant Number: GRC2013-041 European Regional Development Fund Sara Borrell Programme. Grant Number: CD13/00373 ISCIII General Subdirection of Assesment and Promotion of the Research. Grant Number: PI14/00059S

QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes

Type II dehydroquinase enzymes (DHQ2), recognized targets for antibiotic drug discovery, show significantly different activities dependent on the species: DHQ2 from Mycobacterium tuberculosis (MtDHQ2) and Helicobacter pylori (HpDHQ2) show a 50-fold difference in catalytic efficiency. Revealing the determinants of this activity difference is important for our understanding of biological catalysis and further offers the potential to contribute to tailoring specificity in drug design. Molecular dynamics simulations using a quantum mechanics/molecular mechanics potential, with correlated ab initio single point corrections, identify and quantify the subtle determinants of the experimentally observed difference in efficiency. The rate-determining step involves the formation of an enolate intermediate: more efficient stabilization of the enolate and transition state of the key step in MtDHQ2, mainly by the essential residues Tyr24 and Arg19, makes it more efficient than HpDHQ2. Further, a water molecule, which is absent in MtDHQ2 but involved in generation of the catalytic Tyr22 tyrosinate in HpDHQ2, was found to destabilize both the transition state and the enolate intermediate. The quantification of the contribution of key residues and water molecules in the rate-determining step of the mechanism also leads to improved understanding of higher potencies and specificity of known inhibitors, which should aid ongoing inhibitor design.</p

Characterization of Locally Excited and Charge-Transfer States of the Anticancer Drug Lapatinib by Ultrafast Spectroscopy and Computational Studies

This is the peer reviewed version of the following article: I. Vayá, I. Andreu, E. Lence, C. González-Bello, M. Consuelo Cuquerella, M. Navarrete-Miguel, D. Roca-Sanjuán, M. A. Miranda, Chem. Eur. J. 2020, 26, 15922, which has been published in final form at https://doi.org/10.1002/chem.202001336. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] Lapatinib (LAP) is an anticancer drug, which is metabolized to theN- and O-dealkylated products (N-LAP andO-LAP, respectively). In view of the photosensitizing potential of related drugs, a complete experimental and theoretical study has been performed on LAP,N-LAP andO-LAP, both in solution and upon complexation with human serum albumin (HSA). In organic solvents, coplanar locally excited (LE) emissive states are generated; they rapidly evolve towards twisted intramolecular charge-transfer (ICT) states. By contrast, within HSA only LE states are detected. Accordingly, femtosecond transient absorption reveals a very fast switching (ca. 2 ps) from LE (lambda(max)=550 nm) to ICT states (lambda(max)=480 nm) in solution, whereas within HSA the LE species become stabilized and live much longer (up to the ns scale). Interestingly, molecular dynamics simulation studies confirm that the coplanar orientation is preferred for LAP (or to a lesser extentN-LAP) within HSA, explaining the experimental results.Financial support from the Spanish Government (RYC-2015-17737, CTQ2017-89416-R, ISCIII grants RD16/0006/0004, PI16/01877 and CPII16/00052, SAF2016-75638-R, RYC-2015-19234, CTQ2017-87054-C2-2-P, and MDM-2015-0538), Conselleria d'Educacio Cultura i Esport (PROMETEO/2017/075), the Xunta de Galicia [ED431B 2018/04 and Centro singular de investigacion de Galicia accreditation 2019-2022 (ED431G 2019/03)] and the European Regional Development Fund is gratefully acknowledged. We thank the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer.Vayá Pérez, I.; Andreu Ros, MI.; Lence, E.; González-Bello, C.; Cuquerella Alabort, MC.; Navarrete-Miguel, M.; Roca-Sanjuán, D.... (2020). Characterization of Locally Excited and Charge-Transfer States of the Anticancer Drug Lapatinib by Ultrafast Spectroscopy and Computational Studies. Chemistry - A European Journal. 26(68):15922-15930. https://doi.org/10.1002/chem.202001336S15922159302668Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394-424. doi:10.3322/caac.21492Nicholson, R. ., Gee, J. M. ., & Harper, M. . (2001). EGFR and cancer prognosis. European Journal of Cancer, 37, 9-15. doi:10.1016/s0959-8049(01)00231-3Yashiro, M., Qiu, H., Hasegawa, T., Zhang, X., Matsuzaki, T., & Hirakawa, K. (2011). An EGFR inhibitor enhances the efficacy of SN38, an active metabolite of irinotecan, in SN38-refractory gastric carcinoma cells. British Journal of Cancer, 105(10), 1522-1532. doi:10.1038/bjc.2011.397Gonzalez, G., & Lage, A. (2007). Cancer Vaccines for Hormone/Growth Factor Immune Deprivation:A Feasible Approach for Cancer Treatment. Current Cancer Drug Targets, 7(3), 229-241. doi:10.2174/156800907780618310Sigismund, S., Avanzato, D., & Lanzetti, L. (2017). Emerging functions of the EGFR in cancer. Molecular Oncology, 12(1), 3-20. doi:10.1002/1878-0261.12155Thomas, R., & Weihua, Z. (2019). Rethink of EGFR in Cancer With Its Kinase Independent Function on Board. Frontiers in Oncology, 9. doi:10.3389/fonc.2019.00800MEDINA, P., & GOODIN, S. (2008). Lapatinib: A dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clinical Therapeutics, 30(8), 1426-1447. doi:10.1016/j.clinthera.2008.08.008Nolting, M., Schneider-Merck, T., & Trepel, M. (2014). Lapatinib. Small Molecules in Oncology, 125-143. doi:10.1007/978-3-642-54490-3_7Schroeder, R., Stevens, C., & Sridhar, J. (2014). Small Molecule Tyrosine Kinase Inhibitors of ErbB2/HER2/Neu in the Treatment of Aggressive Breast Cancer. Molecules, 19(9), 15196-15212. doi:10.3390/molecules190915196Spector, N. L., Xia, W., Burris, H., Hurwitz, H., Dees, E. C., Dowlati, A., … Bacus, S. (2005). Study of the Biologic Effects of Lapatinib, a Reversible Inhibitor of ErbB1 and ErbB2 Tyrosine Kinases, on Tumor Growth and Survival Pathways in Patients With Advanced Malignancies. Journal of Clinical Oncology, 23(11), 2502-2512. doi:10.1200/jco.2005.12.157Krasner, J. (1972). Drug-Protein Interaction. Pediatric Clinics of North America, 19(1), 51-63. doi:10.1016/s0031-3955(16)32666-9Peters, T. (1995). Ligand Binding by Albumin. All About Albumin, 76-132. doi:10.1016/b978-012552110-9/50005-2Molins-Molina, O., Lence, E., Limones-Herrero, D., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2019). Identification of a common recognition center for a photoactive non-steroidal antiinflammatory drug in serum albumins of different species. Organic Chemistry Frontiers, 6(1), 99-109. doi:10.1039/c8qo01045eMolins-Molina, O., Pérez-Ruiz, R., Lence, E., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2019). Photobinding of Triflusal to Human Serum Albumin Investigated by Fluorescence, Proteomic Analysis, and Computational Studies. Frontiers in Pharmacology, 10. doi:10.3389/fphar.2019.01028Monteiro, A. F., Rato, M., & Martins, C. (2016). Drug-induced photosensitivity: Photoallergic and phototoxic reactions. Clinics in Dermatology, 34(5), 571-581. doi:10.1016/j.clindermatol.2016.05.006Vayá, I., Andreu, I., Monje, V. T., Jiménez, M. C., & Miranda, M. A. (2015). Mechanistic Studies on the Photoallergy Mediated by Fenofibric Acid: Photoreactivity with Serum Albumins. Chemical Research in Toxicology, 29(1), 40-46. doi:10.1021/acs.chemrestox.5b00357Vayá, I., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2014). Photoactive assemblies of organic compounds and biomolecules: drug–protein supramolecular systems. Chem. Soc. Rev., 43(12), 4102-4122. doi:10.1039/c3cs60413fIshikawa, T., Kamide, R., & Niimura, M. (1994). Photoleukomelanodermatitis (Kobori) Induced by Afloqualone. The Journal of Dermatology, 21(6), 430-433. doi:10.1111/j.1346-8138.1994.tb01768.xKabir, M. Z., Mukarram, A. K., Mohamad, S. B., Alias, Z., & Tayyab, S. (2016). Characterization of the binding of an anticancer drug, lapatinib to human serum albumin. Journal of Photochemistry and Photobiology B: Biology, 160, 229-239. doi:10.1016/j.jphotobiol.2016.04.005Shen, G.-F., Liu, T.-T., Wang, Q., Jiang, M., & Shi, J.-H. (2015). Spectroscopic and molecular docking studies of binding interaction of gefitinib, lapatinib and sunitinib with bovine serum albumin (BSA). Journal of Photochemistry and Photobiology B: Biology, 153, 380-390. doi:10.1016/j.jphotobiol.2015.10.023Wilson, J. N., Liu, W., Brown, A. S., & Landgraf, R. (2015). Binding-induced, turn-on fluorescence of the EGFR/ERBB kinase inhibitor, lapatinib. Organic & Biomolecular Chemistry, 13(17), 5006-5011. doi:10.1039/c5ob00239gLi, M.-D., Yan, Z., Zhu, R., Phillips, D. L., Aparici-Espert, I., Lhiaubet-Vallet, V., & Miranda, M. A. (2018). Enhanced Drug Photosafety by Interchromophoric Interaction Owing to Intramolecular Charge Separation. Chemistry - A European Journal, 24(25), 6654-6659. doi:10.1002/chem.201800716Vayá, I., Bonancía, P., Jiménez, M. C., Markovitsi, D., Gustavsson, T., & Miranda, M. A. (2013). Excited state interactions between flurbiprofen and tryptophan in drug–protein complexes and in model dyads. Fluorescence studies from the femtosecond to the nanosecond time domains. Physical Chemistry Chemical Physics, 15(13), 4727. doi:10.1039/c3cp43847cAndersson, K., Malmqvist, P., & Roos, B. O. (1992). Second‐order perturbation theory with a complete active space self‐consistent field reference function. The Journal of Chemical Physics, 96(2), 1218-1226. doi:10.1063/1.462209Andersson, K., Malmqvist, P. A., Roos, B. O., Sadlej, A. J., & Wolinski, K. (1990). Second-order perturbation theory with a CASSCF reference function. The Journal of Physical Chemistry, 94(14), 5483-5488. doi:10.1021/j100377a012Roca-Sanjuán, D., Aquilante, F., & Lindh, R. (2011). Multiconfiguration second-order perturbation theory approach to strong electron correlation in chemistry and photochemistry. Wiley Interdisciplinary Reviews: Computational Molecular Science, 2(4), 585-603. doi:10.1002/wcms.97In:http://www.ccdc.cam.ac.uk/solutions/csd-discovery/components/gold/(accessed January 22 2020).Zunszain, P. A., Ghuman, J., Komatsu, T., Tsuchida, E., & Curry, S. (2003). BMC Structural Biology, 3(1), 6. doi:10.1186/1472-6807-3-6D. A. Case R. M. Betz D. S. Cerutti T. E. Cheatham T. A. Darden R. E. Duke T. J. Giese H. Gohlke A. W. Goetz N. Homeyer S. Izadi P. Janowski J. J. Kaus A. Kovalenko T. S. Lee S. LeGrand P. Li C. Lin T. Luchko R. Luo B. Madej D. Mermelstein K. M. M. Merz G. Monard H. Nguyen H. Nguyen I. Omelyan A. Onufriev D. R. R. Roe A. Roitberg C. Sagui C. L. Simmerling W. M. Botello-Smith J. Swails R. Walker J. Wang R. M. Wolf X. Wu L. Xiao P. A. Kollman AMBER2016 University of California San Francisco.Wybranowski, T., Cyrankiewicz, M., Ziomkowska, B., & Kruszewski, S. (2008). The HSA affinity of warfarin and flurbiprofen determined by fluorescence anisotropy measurements of camptothecin. Biosystems, 94(3), 258-262. doi:10.1016/j.biosystems.2008.05.034Itoh, T., Saura, Y., Tsuda, Y., & Yamada, H. (1997). Stereoselectivity and enantiomer-enantiomer interactions in the binding of ibuprofen to human serum albumin. Chirality, 9(7), 643-649. doi:10.1002/(sici)1520-636x(1997)9:73.0.co;2-8Pérez-Ruíz, R., Lence, E., Andreu, I., Limones-Herrero, D., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2017). A New Pathway for Protein Haptenation by β-Lactams. Chemistry - A European Journal, 23(56), 13986-13994. doi:10.1002/chem.201702643Gaussian 09 Revision D.01 M. J. Frisch G. W. Trucks H. B. Schlegel G. E. Scuseria M. A. Robb J. R. Cheeseman G. Scalmani V. Barone B. Mennucci G. A. Petersson H. Nakatsuji M. Caricato X. Li H. P. Hratchian A. F. Izmaylov J. Bloino G. Zheng J. L. Sonnenberg M. Hada M. Ehara K. Toyota R. Fukuda J. Hasegawa M. Ishida T. Nakajima Y. Honda O. Kitao H. Nakai T. Vreven J. J. A. Montgomery J. E. Peralta F. Ogliaro M. Bearpark J. J. Heyd E. Brothers K. N. Kudin V. N. Staroverov R. Kobayashi J. Normand K. Raghavachari A. Rendell J. C. Burant S. S. Iyengar J. Tomasi M. Cossi N. Rega J. M. Millam M. Klene J. E. Knox J. B. Cross V. Bakken C. Adamo J. Jaramillo R. Gomperts R. E. Stratmann O. Yazyev A. J. Austin R. Cammi C. Pomelli J. W. Ochterski R. L. Martin K. Morokuma V. G. Zakrzewski G. A. Voth P. Salvador J. J. Dannenberg S. Dapprich A. D. Daniels Ö. Farkas J. B. Foresman J. V. Ortiz J. Cioslowski D. J. Fox 2013 Wallingford CT.Aquilante, F., Autschbach, J., Carlson, R. K., Chibotaru, L. F., Delcey, M. G., De Vico, L., … Lindh, R. (2015). Molcas 8: New capabilities for multiconfigurational quantum chemical calculations across the periodic table. Journal of Computational Chemistry, 37(5), 506-541. doi:10.1002/jcc.24221Forsberg, N., & Malmqvist, P.-Å. (1997). Multiconfiguration perturbation theory with imaginary level shift. Chemical Physics Letters, 274(1-3), 196-204. doi:10.1016/s0009-2614(97)00669-6W. L. DeLano in The PyMOL Molecular Graphics System.http://www.pymol.org/