000095508 001__ 95508
000095508 005__ 20210902121733.0
000095508 0247_ $$2doi$$a10.1371/journal.pcbi.1007898
000095508 0248_ $$2sideral$$a119580
000095508 037__ $$aART-2020-119580
000095508 041__ $$aeng
000095508 100__ $$aLans, Isaías
000095508 245__ $$aIn silico discovery and biological validation of ligands of FAD synthase, a promising new antimicrobial target
000095508 260__ $$c2020
000095508 5060_ $$aAccess copy available to the general public$$fUnrestricted
000095508 5203_ $$aNew treatments for diseases caused by antimicrobial-resistant microorganisms can be developed by identifying unexplored therapeutic targets and by designing efficient drug screening protocols. In this study, we have screened a library of compounds to find ligands for the flavin-adenine dinucleotide synthase (FADS) -a potential target for drug design against tuberculosis and pneumonia- by implementing a new and efficient virtual screening protocol. The protocol has been developed for the in silico search of ligands of unexplored therapeutic targets, for which limited information about ligands or ligand-receptor structures is available. It implements an integrative funnel-like strategy with filtering layers that increase in computational accuracy. The protocol starts with a pharmacophore-based virtual screening strategy that uses ligand-free receptor conformations from molecular dynamics (MD) simulations. Then, it performs a molecular docking stage using several docking programs and an exponential consensus ranking strategy. The last filter, samples the conformations of compounds bound to the target using MD simulations. The MD conformations are scored using several traditional scoring functions in combination with a newly-proposed score that takes into account the fluctuations of the molecule with a Morse-based potential. The protocol was optimized and validated using a compound library with known ligands of the Corynebacterium ammoniagenes FADS. Then, it was used to find new FADS ligands from a compound library of 14, 000 molecules. A small set of 17 in silico filtered molecules were tested experimentally. We identified five inhibitors of the activity of the flavin adenylyl transferase module of the FADS, and some of them were able to inhibit growth of three bacterial species: C. ammoniagenes, Mycobacterium tuberculosis, and Streptococcus pneumoniae, where the last two are human pathogens. Overall, the results show that the integrative VS protocol is a cost-effective solution for the discovery of ligands of unexplored therapeutic targets.
000095508 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000095508 590__ $$a4.475$$b2020
000095508 591__ $$aMATHEMATICAL & COMPUTATIONAL BIOLOGY$$b8 / 58 = 0.138$$c2020$$dQ1$$eT1
000095508 591__ $$aBIOCHEMICAL RESEARCH METHODS$$b16 / 77 = 0.208$$c2020$$dQ1$$eT1
000095508 592__ $$a2.628$$b2020
000095508 593__ $$aCellular and Molecular Neuroscience$$c2020$$dQ1
000095508 593__ $$aComputational Theory and Mathematics$$c2020$$dQ1
000095508 593__ $$aEcology$$c2020$$dQ1
000095508 593__ $$aMolecular Biology$$c2020$$dQ1
000095508 593__ $$aGenetics$$c2020$$dQ1
000095508 593__ $$aModeling and Simulation$$c2020$$dQ1
000095508 593__ $$aEcology, Evolution, Behavior and Systematics$$c2020$$dQ1
000095508 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000095508 700__ $$0(orcid)0000-0002-6649-9153$$aAnoz-Carbonell, Ernesto$$uUniversidad de Zaragoza
000095508 700__ $$aPalacio-Rodríguez, Karen
000095508 700__ $$0(orcid)0000-0003-2076-844X$$aAínsa, José Antonio$$uUniversidad de Zaragoza
000095508 700__ $$0(orcid)0000-0001-8743-0182$$aMedina, Milagros$$uUniversidad de Zaragoza
000095508 700__ $$aCossio, Pilar
000095508 7102_ $$11011$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Microbiología
000095508 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000095508 773__ $$g16, 8 (2020), e1007898 1-24$$pPLoS Comput. Biol.$$tPLoS computational biology$$x1553-734X
000095508 8564_ $$s2111964$$uhttps://zaguan.unizar.es/record/95508/files/texto_completo.pdf$$yVersión publicada
000095508 8564_ $$s515746$$uhttps://zaguan.unizar.es/record/95508/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000095508 909CO $$ooai:zaguan.unizar.es:95508$$particulos$$pdriver
000095508 951__ $$a2021-09-02-09:37:01
000095508 980__ $$aARTICLE