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      Photobinding of Triflusal to Human Serum Albumin Investigated by Fluorescence, Proteomic Analysis, and Computational Studies

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          Abstract

          Triflusal is a platelet antiaggregant employed for the treatment and prevention of thromboembolic diseases. After administration, it is biotransformed into its active metabolite, the 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). We present here an investigation on HTB photobinding to human serum albumin (HSA), the most abundant protein in plasma, using an approach that combines fluorescence, MS/MS, and peptide fingerprint analysis as well as theoretical calculations (docking and molecular dynamics simulation studies). The proteomic analysis of HTB/HSA photolysates shows that HTB addition takes place at the ε-amino groups of the Lys137, Lys199, Lys205, Lys351, Lys432, Lys525, Lys541 and Lys545 residues and involves replacement of the trifluoromethyl moiety of HTB with a new amide function. Only Lys199 is located in an internal pocket of the protein, and the remaining modified residues are placed in the external part. Docking and molecular dynamic simulation studies reveal that HTB supramolecular binding to HSA occurs in the “V-cleft” region and that the process is assisted by the presence of Glu/Asp residues in the neighborhood of the external Lys, in agreement with the experimentally observed modifications. In principle, photobinding can occur with other trifluoroaromatic compounds and may be responsible for the appearance of undesired photoallergic side effects.

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          H++: a server for estimating pKas and adding missing hydrogens to macromolecules

          The structure and function of macromolecules depend critically on the ionization (protonation) states of their acidic and basic groups. A number of existing practical methods predict protonation equilibrium pK constants of macromolecules based upon their atomic resolution Protein Data Bank (PDB) structures; the calculations are often performed within the framework of the continuum electrostatics model. Unfortunately, these methodologies are complex, involve multiple steps and require considerable investment of effort. Our web server provides access to a tool that automates this process, allowing both experts and novices to quickly obtain estimates of pKs as well as other related characteristics of biomolecules such as isoelectric points, titration curves and energies of protonation microstates. Protons are added to the input structure according to the calculated ionization states of its titratable groups at the user-specified pH; the output is in the PQR (PDB + charges + radii) format. In addition, corresponding coordinate and topology files are generated in the format supported by the molecular modeling package AMBER. The server is intended for a broad community of biochemists, molecular modelers, structural biologists and drug designers; it can also be used as an educational tool in biochemistry courses.
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            Structural basis of the drug-binding specificity of human serum albumin.

            Human serum albumin (HSA) is an abundant plasma protein that binds a remarkably wide range of drugs, thereby restricting their free, active concentrations. The problem of overcoming the binding affinity of lead compounds for HSA represents a major challenge in drug development. Crystallographic analysis of 17 different complexes of HSA with a wide variety of drugs and small-molecule toxins reveals the precise architecture of the two primary drug-binding sites on the protein, identifying residues that are key determinants of binding specificity and illuminating the capacity of both pockets for flexible accommodation. Numerous secondary binding sites for drugs distributed across the protein have also been identified. The binding of fatty acids, the primary physiological ligand for the protein, is shown to alter the polarity and increase the volume of drug site 1. These results clarify the interpretation of accumulated drug binding data and provide a valuable template for design efforts to modulate the interaction with HSA.
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              The R.E.D. tools: advances in RESP and ESP charge derivation and force field library building.

              Deriving atomic charges and building a force field library for a new molecule are key steps when developing a force field required for conducting structural and energy-based analysis using molecular mechanics. Derivation of popular RESP charges for a set of residues is a complex and error prone procedure because it depends on numerous input parameters. To overcome these problems, the R.E.D. Tools (RESP and ESP charge Derive, ) have been developed to perform charge derivation in an automatic and straightforward way. The R.E.D. program handles chemical elements up to bromine in the periodic table. It interfaces different quantum mechanical programs employed for geometry optimization and computing molecular electrostatic potential(s), and performs charge fitting using the RESP program. By defining tight optimization criteria and by controlling the molecular orientation of each optimized geometry, charge values are reproduced at any computer platform with an accuracy of 0.0001 e. The charges can be fitted using multiple conformations, making them suitable for molecular dynamics simulations. R.E.D. allows also for defining charge constraints during multiple molecule charge fitting, which are used to derive charges for molecular fragments. Finally, R.E.D. incorporates charges into a force field library, readily usable in molecular dynamics computer packages. For complex cases, such as a set of homologous molecules belonging to a common family, an entire force field topology database is generated. Currently, the atomic charges and force field libraries have been developed for more than fifty model systems and stored in the RESP ESP charge DDataBase. Selected results related to non-polarizable charge models are presented and discussed.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                20 September 2019
                2019
                : 10
                : 1028
                Affiliations
                [1] 1Departamento de Química/Instituto de Tecnología Química UPV-CSIC, Universitat Politécnica de València , Valencia, Spain
                [2] 2Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela , Santiago de Compostela, Spain
                Author notes

                Edited by: Ke-Vin Chang, National Taiwan University Hospital, Taiwan

                Reviewed by: Oksana Lockridge, University of Nebraska Medical Center, United States; Xiaoli Meng, University of Liverpool, United Kingdom

                *Correspondence: Miguel A. Miranda, mmiranda@ 123456qim.upv.es ; Maria Consuelo Jiménez, mcjimene@ 123456qim.upv.es

                This article was submitted to Translational Pharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2019.01028
                6764118
                9dc7ac50-9842-4d9e-ba23-bc2b143b24d4
                Copyright © 2019 Molins-Molina, Pérez-Ruiz, Lence, González-Bello, Miranda and Jiménez

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 May 2019
                : 12 August 2019
                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 65, Pages: 9, Words: 4526
                Funding
                Funded by: Ministerio de Economía, Industria y Competitividad, Gobierno de España 10.13039/501100010198
                Award ID: CTQ2016-78875-P, SAF2016-75638-R, BES‐2014‐069404
                Funded by: Generalitat Valenciana 10.13039/501100003359
                Award ID: PROMETEO/2017/075, CIDEGENT/2018/044
                Funded by: Xunta de Galicia 10.13039/501100010801
                Award ID: ED431G/09, ED431B 2018/04
                Funded by: Instituto de Salud Carlos III 10.13039/501100004587
                Award ID: RETICS network ARADyAL RD16/0006/0030
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                triflusal metabolite,human serum albumin,fluorescence,proteomic analysis,docking and molecular dynamics

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