Extending the frontiers in biomolecular interactions: docking and free energy assessment

Abstract

The number of gene products that can be regulated by drugs, the druggable genome, is estimated in 3051. However, the drugs already in market target only 266 gene products. With the rapid advances in structural biology it is attractive to use this structural information for the development of new chemical probes looking for biological function modulation. Two challenges in this context are the correct selection of compounds able to interact with a biological macromolecule and the evaluation of the affinity for this receptor-ligand complex. In this project we propose the development of a computational tool combining the strategies based on receptor structures with those based on the bioactive ligand structure for the proposition of new candidate ligands. The same tool is also used for the generation of ensembles for the binding free energy evaluation. This model will be applied for a model system (T4 lysozyme), as well as for nuclear receptors involved in human metabolism regulation. (AU)

Scientific publications

(12)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MALTAROLLO, VINICIUS G.; TOGASHI, MARIE; NASCIMENTO, ALESSANDRO S.; HONORIO, KATHIA M.. Structure-Based Virtual Screening and Discovery of New PPAR delta/gamma Dual Agonist and PPAR delta and gamma Agonists. PLoS One, v. 10, n. 3, MAR 13 2015. (11/18981-2, 14/06565-2)

FLORINDO, RENATA N.; SOUZA, VALQUIRIA P.; MANZINE, LIVIA R.; CAMILO, CESAR M.; MARANA, SANDRO R.; POLIKARPOV, IGOR; NASCIMENTO, ALESSANDRO S.. Structural and biochemical characterization of a GH3 beta-glucosidase from the probiotic bacteria Bifidobacterium adolescentis. Biochimie, v. 148, p. 107-115, MAY 2018. (14/19439-5, 08/56255-9, 14/06565-2)

MUNIZ, HELOISA DOS SANTOS; NASCIMENTO, ALESSANDRO S.. Ligand- and receptor-based docking with LiBELa. Journal of Computer-Aided Molecular Design, v. 29, n. 8, p. 713-723, AUG 2015. (14/06565-2)

FARRO, ERICK GIANCARLO S.; LEITE, ANA ELISA T.; SILVA, ISABELA A.; FILGUEIRAS, JEFFERSON G.; DE AZEVEDO, EDUARDO R.; POLIKARPOV, IGOR; NASCIMENTO, ALESSANDRO S.. GH43 endo-arabinanase from Bacillus licheniformis: Structure, activity and unexpected synergistic effect on cellulose enzymatic hydrolysis. International Journal of Biological Macromolecules, v. 117, p. 7-16, OCT 1 2018. (14/06565-2, 15/13684-0, 14/03768-0)

DE SOUZA, JOAO VICTOR; NOGUEIRA, VICTOR H. R.; NASCIMENTO, ALESSANDRO S.. Ligand binding free energy evaluation by Monte Carlo Recursion. COMPUTATIONAL BIOLOGY AND CHEMISTRY, v. 103, p. 12-pg., 2023-02-20. (17/18173-0, 20/03983-9, 14/06565-2, 10/15376-8, 14/01751-2, 15/01709-9, 15/26722-8)

GODOY, ANDRE SCHUTZER; CAMILO, CESAR MOISES; KADOWAKI, MARCO ANTONIO; MUNIZ, HELOISA DOS S.; SANTO, MELISSA ESPIRITO; MURAKAMI, MARIO TYAGO; NASCIMENTO, ALESSANDRO S.; POLIKARPOV, IGOR. Crystal structure of beta 1 -> 6-galactosidase from Bifidobacterium bifidum S17: trimeric architecture, molecular determinants of the enzymatic activity and its inhibition by alpha-galactose. FEBS Journal, v. 283, n. 22, p. 4097-4112, NOV 2016. (09/52840-7, 11/20505-4, 08/56255-9, 09/05328-9, 14/06565-2, 11/05712-3)

FLORINDO, RENATA N.; SOUZA, VALQUIRIA P.; MUTTI, HEMILY S.; CAMILO, CESAR; MANZINE, LIVIA REGINA; MARANA, SANDRO R.; POLIKARPOV, IGOR; NASCIMENTO, ALESSANDRO S.. Structural insights into beta-glucosidase transglycosylation based on biochemical, structural and computational analysis of two GH1 enzymes from Trichoderma harzianum. NEW BIOTECHNOLOGY, v. 40, n. B, p. 218-227, JAN 25 2017. (14/19439-5, 08/56255-9, 14/06565-2)

DE PAULA, KARINA; SANTOS, JADEMILSON C.; MAFUD, ANA CAROLINA; NASCIMENTO, ALESSANDRO S.. Tetrazoles as PPAR gamma ligands: A structural and computational investigation. JOURNAL OF MOLECULAR GRAPHICS & MODELLING, v. 106, JUL 2021. (10/15376-8, 20/03983-9, 14/06565-2, 15/26722-8)

GODOY, ANDRE SCHUTZER; CAMILO, CESAR MOISES; KADOWAKI, MARCO ANTONIO; MUNIZ, HELOISA DOS S.; SANTO, MELISSA ESPIRITO; MURAKAMI, MARIO TYAGO; NASCIMENTO, ALESSANDRO S.; POLIKARPOV, IGOR. Crystal structure of beta 1 -> 6-galactosidase from Bifidobacterium bifidum S17: trimeric architecture, molecular determinants of the enzymatic activity and its inhibition by alpha-galactose. FEBS Journal, v. 283, n. 22, p. 16-pg., 2016-11-01. (11/05712-3, 09/52840-7, 11/20505-4, 14/06565-2, 08/56255-9, 09/05328-9)

FLORINDO, RENATA N.; SOUZA, VALQUIRIA P.; MUTTI, HEMILY S.; CAMILO, CESAR; MANZINE, LIVIA REGINA; MARANA, SANDRO R.; POLIKARPOV, IGOR; NASCIMENTO, ALESSANDRO S.. Structural insights into beta-glucosidase transglycosylation based on biochemical, structural and computational analysis of two GH1 enzymes from Trichoderma harzianum. NEW BIOTECHNOLOGY, v. 40, p. 10-pg., 2018-01-25. (14/19439-5, 08/56255-9, 14/06565-2)

SONODA, MILTON T.; GODOY, ANDRE S.; PELLEGRINI, VANESSA O. A.; KADOWAKI, MARCO A. S.; NASCIMENTO, ALESSANDRO S.; POLIKARPOV, IGOR. Structure and dynamics of Trichoderma harzianum Cel7B suggest molecular architecture adaptations required for a wide spectrum of activities on plant cell wall polysaccharides. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1863, n. 6, p. 1015-1026, JUN 2019. (14/06565-2, 15/13684-0, 17/18173-0)

MUNIZ, HELOISA S.; NASCIMENTO, ALESSANDRO S.. Towards a critical evaluation of an empirical and volume-based solvation function for ligand docking. PLoS One, v. 12, n. 3, MAR 21 2017. (14/06565-2, 10/15376-8)