Computational biochemical investigation of the binding energy interactions between an estrogen receptor and its agonists

Costa, Aranthya H. Lima; Clemente, Washington Sales; Neto, José Xavier; Albuquerque, E.L.; Fulco, U. L.

doi:10.1039/c8nj03521k

Cited by 13 publications

(6 citation statements)

References 70 publications

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“…However, it is well-known that the length and intensity in each of these interactions presents a range that can be slightly higher or shorter depending on the angle formed and the atoms involved. Therefore, to properly evaluate the coupling of the ligands, we perform a search for an optimal binding site radius, adding the individual interaction energies of those amino acid residues within imaginary spheres with a pocket radius r centered at the ligand, according to ref .…”

Section: Resultsmentioning

confidence: 99%

Exploring the Binding Mechanism of GABA_B Receptor Agonists and Antagonists through in Silico Simulations

Neto

Barbosa

Manzoni

et al. 2019

J. Chem. Inf. Model.

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GABA B is a G protein-coupled receptor that functions as a constitutive heterodimer composed of the GABA B1a/b and GABA B2 subunits. It mediates slow and prolonged inhibitory neurotransmission in the nervous system, representing an attractive target for the treatment of various disorders. However, the molecular mechanism of the GABA B receptor is not thoroughly understood. Therefore, a better description of the binding of existing agonists and antagonists to this receptor is crucial to improve our knowledge about G protein-coupled receptor structure as well as for helping the development of new potent and more selective therapeutic agents. In this work, we used the recent X-ray cocrystallization data of agonists (GABA and baclofen) and antagonists (2-hydroxysaclofen, SCH50911, and CGP54626) bound to the GABA B orthosteric site together with quantum biochemistry and the molecular fractionation with conjugate caps (MFCC) scheme to describe the individual contribution of each amino acid residue involved in the GABA B −ligand interaction, pointing out differences and similarities among the compounds. Our quantum biochemical computational results show that the total binding energy of the ligands to the GABA B ligand pocket, with radius varying from 2.0 to 9.0 Å, is well-correlated with the experimental binding affinity. In addition, we found that the binding site is very similar for agonists or antagonists, showing small differences in the importance of the most significant amino acids. Finally, we predict the energetic relevance of the regions of the five ligands as well as the influence of each protein lobe on GABA B −ligand binding. These results provide important new information on the binding mechanism of the GABA B receptor and should facilitate the development of new chemicals targeting this receptor.

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Section: Resultsmentioning

confidence: 99%

Exploring the Binding Mechanism of GABA_B Receptor Agonists and Antagonists through in Silico Simulations

Neto

Barbosa

Manzoni

et al. 2019

J. Chem. Inf. Model.

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“…Therefore, we characterize the ligands as L , and the amino acid residue that interacts with the ligands as R i , with i indicating the index of amino acid residue i -th. The cap C i ( C i * ) is structured by the neighboring residue covalently bonded to the amine group (carboxyl) of the residue R i through the protein chain, providing a better description of its electronic environment. ,− For these fragmented structures, energy calculations based on DFT were performed, and the interaction energy between the ligand and the individual fragment, IE MFCC ( L – R i ), was calculated according to .25ex2ex normalI E MFCC ( L − R i ) = E ( L − C i R i C i * ) − E ( C i R i C i * ) infix− E ( L − C i C i * ) + E ( C i C i * ) , where the first term, E ( L – C i R i C i * ), corresponds to the total energy of the system composed of the binder and the capped residue; the second term, E ( C i R i C i * ), is the total energy of the residue with caps; the third term, E ( L – C i C i * ), is the total energy of the system formed by the caps and the ligand; the fourth and last term, E ( C i C i * ), is the energy of caps with the dangling bonds passivated by hydrogen. Furthermore, in this strategy, water molecules contained in the crystallographic structure were explicitly considered in the calculation, being associated with residue R i or one of its caps when a hydrogen bond (H-bond) is formed between them.…”

Section: Methodsmentioning

confidence: 99%

Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective

Lima Costa,

Bezerra,

de Lima Neto

et al. 2023

J. Phys. Chem. B

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Malaria is a parasitic disease that, in its most severe form, can even lead to death. Insect-resistant vectors, insufficiently effective vaccines, and drugs that cannot stop parasitic infestations are making the fight against the disease increasingly difficult. It is known that the enzyme dihydroorotate dehydrogenase (DHODH) is of paramount importance for the synthesis of pyrimidine from the Plasmodium precursor, that is, for its growth and reproduction. Therefore, its blockade can lead to disruption of the parasite's life cycle in the vertebrate host. In this scenario, Pf DHODH inhibitors have been considered candidates for a new therapy to stop the parasitic energy source. Given what is known, in this work, we applied molecular fractionation with conjugated caps (MFCC) in the framework of the quantum formalism of density functional theory (DFT) to evaluate the energies of the interactions between the enzyme and the different triazolopyrimidines (DSM483, DMS557, and DSM1), including a complex carrying the mutation C276F. From these results, it was possible to identify the main features of each system, focusing on the wild-type and mutant Pf DHODH and examining the major amino acid residues that are part of the four complexes. Our analysis provides new information that can be used to develop new drugs that could prove to be more effective alternatives to present antimalarial drugs.

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“…To analyze the changes in the investigated complexes upon DNA binding, not only MM, as with estradiol and DNA [125], but also MD has been applied [126]. The latter study identified specific bases within the aptamer (short-stranded DNA/RNA, binds only specific molecules [127]) and demonstrated the importance of water-mediated hydrogen bonds in the aptamer-estradiol complex.…”

Section: Quantitative Structure-activity Relationship (Qsar)mentioning

confidence: 99%

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

Mazurek

Szeleszczuk

Simonson

et al. 2020

IJMS

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In this review, applications of various molecular modelling methods in the study of estrogens and xenoestrogens are summarized. Selected biomolecules that are the most commonly chosen as molecular modelling objects in this field are presented. In most of the reviewed works, ligand docking using solely force field methods was performed, employing various molecular targets involved in metabolism and action of estrogens. Other molecular modelling methods such as molecular dynamics and combined quantum mechanics with molecular mechanics have also been successfully used to predict the properties of estrogens and xenoestrogens. Among published works, a great number also focused on the application of different types of quantitative structure–activity relationship (QSAR) analyses to examine estrogen’s structures and activities. Although the interactions between estrogens and xenoestrogens with various proteins are the most commonly studied, other aspects such as penetration of estrogens through lipid bilayers or their ability to adsorb on different materials are also explored using theoretical calculations. Apart from molecular mechanics and statistical methods, quantum mechanics calculations are also employed in the studies of estrogens and xenoestrogens. Their applications include computation of spectroscopic properties, both vibrational and Nuclear Magnetic Resonance (NMR), and also in quantum molecular dynamics simulations and crystal structure prediction. The main aim of this review is to present the great potential and versatility of various molecular modelling methods in the studies on estrogens and xenoestrogens.

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Computational biochemical investigation of the binding energy interactions between an estrogen receptor and its agonists

Abstract: We present the energy profiles of estrogen receptor–agonist ligand interactions in atomic detail using a quantum biochemical approach.

Cited by 13 publications

References 70 publications

Exploring the Binding Mechanism of GABA_B Receptor Agonists and Antagonists through in Silico Simulations

Exploring the Binding Mechanism of GABA_B Receptor Agonists and Antagonists through in Silico Simulations

Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

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Computational biochemical investigation of the binding energy interactions between an estrogen receptor and its agonists

Abstract: We present the energy profiles of estrogen receptor–agonist ligand interactions in atomic detail using a quantum biochemical approach.

Cited by 13 publications

References 70 publications

Exploring the Binding Mechanism of GABAB Receptor Agonists and Antagonists through in Silico Simulations

Exploring the Binding Mechanism of GABAB Receptor Agonists and Antagonists through in Silico Simulations

Deciphering Interactions between Potential Inhibitors and the Plasmodium falciparum DHODH Enzyme: A Computational Perspective

Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

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Product

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Exploring the Binding Mechanism of GABA_B Receptor Agonists and Antagonists through in Silico Simulations

Exploring the Binding Mechanism of GABA_B Receptor Agonists and Antagonists through in Silico Simulations