New designs for inhibitors of the NF-κB: DNA binding

Fernandes, Pedro Augusto Carlos Magno; Henriques, Elsa S.; Pande, Vineet; Ramos, María J.; Maia, Alexandra S.; Almeida, André; Silva, Bruno F. B.; Ribeiro, Carla M. S.; Ribeiro, César F. B.; Ribeiro, David S.M.; Fonseca, Diana A. P.; Cunha, Eva M. S.; Maia, Filipe R. N. C.; Pereira, Joana A. A.; Pacheco, João G.; Ferreira, Joaquim A.A.D.; Matos, Liliana; Pinto, Manuel A. B. P.; Borges, Maria C. S.; Magalhães, Paulo J. C. R.; Teixeira, Pedro Filipe; Veloso, Pedro N. B. C.; Ferreira, Ricarte J. F.; Gomes, Sílvia Cristina Vieira; Barros, Tiago; Selão, Tiago S. J. T.; Fernandes, Virgínia M. M. C.

doi:10.1007/s00214-005-0628-1

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“…Here we present a rational optimization study of the available inhibitor of ABAD, based on the introduction of chemical modifications aimed to improve its binding affinity to the enzyme. Similar strategies were previously proved to be successful in delineating new ways for lead optimization 17–20. The molecular mechanics–Poisson–Boltzmann surface area (MM‐PBSA) methodological approach was used to predict the free binding energy of the different modified inhibitor‐NAD‐enzyme complexes.…”

Section: Introductionmentioning

confidence: 99%

Computational optimization of AG18051 inhibitor for amyloid‐β binding alcohol dehydrogenase enzyme

Marques

Antunes

Fernandes

et al. 2008

Int J of Quantum Chemistry

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Amyloid-beta (A␤) binding alcohol dehydrogenase (ABAD) is a multifunctional enzyme involved in maintaining the homeostasis. The enzyme can also mediate some diseases, including genetic diseases, Alzheimer's disease, and possibly some prostate cancers. Potent inhibitors of ABAD might facilitate a better clarification of the functions of the enzyme under normal and pathogenic conditions and might also be used for therapeutic intervention in disease conditions mediated by the enzyme. The AG18051 is the only presently available inhibitor of ABAD. It binds in the active-site cavity of the enzyme and reacts with the NAD ϩ cofactor to form a covalent adduct. In this work, we use computational methods to perform a rational optimization of the AG18051 inhibitor, through the introduction of chemical substitutions directed to improve the affinity of the inhibitor to the enzyme. The molecular mechanics-Poisson-Boltzmann surface area methodology was used to predict the relative free binding energy of the different modified inhibitor-NAD-enzyme complexes. We show that it is possible to increase significantly the affinity of the inhibitor to the enzyme with small modifications, without changing the overall structure and ADME (absorption, distribution, metabolism, and excretion) properties of the original inhibitor.

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Section: Introductionmentioning

confidence: 99%