Virtual screening, docking, and dynamics of potential new inhibitors of dihydrofolate reductase from <i>Yersinia pestis</i>

Bastos, Leonardo da Costa; Souza, Felipe Rodrigues de; Guimarães, Ana P.; Sirouspour, Mehdi; Cuya, Teobaldo; Forgione, Pat; Ramalho, Teodorico C.; França, Tanos C. C.

doi:10.1080/07391102.2015.1110832

Cited by 15 publications

(8 citation statements)

References 46 publications

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“…The three-dimensional structures of each oxime, guided by previous results, had the partial atomic charge calculation performed in Spartan 08 Suite using the semiempirical method RM1. − …”

Section: Methodsmentioning

confidence: 99%

Molecular Modeling Study of Uncharged Oximes Compared to HI-6 and 2-PAM Inside Human AChE Sarin and VX Conjugates

et al. 2020

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The deleterious effects of nerve agents over the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) turned these compounds into the most dangerous chemical weapons known. Among the antidotes in use today against these agents, oximes in combination with other drugs are the only treatment with any action. HI-6 and 2-PAM are cationic oximes proved to be effective for the reactivation of AChE inhibited by the nerve agents VX and sarin (GB). However, when it comes to reactivation of AChE inside the central or peripheral nervous systems, charged molecules present low diffusion due to low penetration through the blood−brain barrier. Uncharged oximes appear as an interesting alternative to solve this problem, but the development and enhancement of more efficient uncharged oximes capable of reactivating human AChE is still necessary. Given the limitations for in vivo and in vitro experimental studies with nerve agents, modeling is an important tool that can contribute to a better understanding of factors that may affect the efficiency of uncharged oximes. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed here molecular docking, molecular dynamics simulations, and binding energies calculations of the known cationic oximes HI-6 and 2-PAM plus four uncharged oximes found in the literature, complexed with human AChE (HssACHE) conjugated with the nerve agents VX and GB. The uncharged oximes showed different behaviors, especially RS194B, which presented stability inside AChE-VX, but presented free binding energy lower than cationic oximes, suggesting that structural alterations could favor its interactions with these complexes. In contrast, HI-6 and 2-PAM showed higher affinities with more negative binding energy values and larger contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of oximes with AChE-GB and AChE-VX conjugates.

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Section: Methodsmentioning

confidence: 99%

Molecular Modeling Study of Uncharged Oximes Compared to HI-6 and 2-PAM Inside Human AChE Sarin and VX Conjugates

et al. 2020

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“…X‐ray crystallographic structure of human dihydrofolate reductase (PDB ID 4QHV) was obtained from RCSB Protein Data Bank and used as a reference to identify the cavity of the enzyme. Some important residues involved in protein‐ligand interactions have been reported by previous X‐ray studies . In order not to miss any of these critical residues, we used a cutoff 10 Å from the center of N 6 ‐methyl‐N 6 ‐(4‐isopropylphenyl) pyrido [2,3‐d] pyrimidine‐2,4,6‐triamine inhibitor to determine ligand‐interacting residues.…”

Section: Methodsmentioning

confidence: 99%

“…Some important residues involved in protein-ligand interactions have been reported by previous X-ray studies. [51][52][53] In order not to miss any of these critical residues, we used a cutoff 10 Å from the center of N 6 -methyl-N 6 -(4-isopropylphenyl) pyrido [2,3-d] pyrimidine-2,4,6triamine inhibitor to determine ligand-interacting residues. Seventy-six residues have been identified this way.…”

Section: Descriptor Of Receptorsmentioning

confidence: 99%

Probing the origin of dihydrofolate reductase inhibition via proteochemometric modeling

Hariri

Ghasemi

Shirini

et al. 2018

Journal of Chemometrics

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Dihydrofolate reductase (DHFR) is an essential enzyme in the folate metabolism pathway and an important target of antineoplastic, antimicrobial, antiprotozoal, and antiinflammatory drugs. Despite the clinical effectiveness of current antifolate treatments, new drugs are needed to be designed due to developing resistance of this enzyme through multiple‐site mutagenesis. Understanding the factors affecting the ligand binding selectivity profiles among DHFR families is critical for the design of novel potent and selective inhibitors, with the least side effects, against DHFR of pathogens. Hybrid scaffolds containing pyrimidine ring are effective in DHFR inhibition. In this study, using proteochemometric (PCM) modeling, we designed and evaluated new potent pyrimidine scaffold‐based inhibitors via 3‐dimensional alignment‐free GRid‐INdependent Descriptors (GRIND), VolSurf molecular, and sequence‐based (z‐scale) descriptors to provide ligand and receptor descriptors, respectively. Validation and robustness of the model were confirmed by venetian blinds cross‐validation and Y‐scrambling approaches, respectively. Applicability domain (AD) analysis was performed to estimate the likelihood of reliable prediction for compounds. To show the applicability of the PCM model, new ligands were designed using structural data retrieved from this model. Inhibitory activities of the designs were then predicted, and selectivity ratio profiles were investigated. Finally, potent and highly selective inhibitors were identified regarding the protozoan parasite Toxoplasma gondii, followed by evaluating the ADMET parameters of the ligands.

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“…Despite the declaration of the World Health Organization (WHO) that the Variola virus was eradicated from the world by the 1980s, smallpox is still a matter of concern. Moreover, many studies on the development of drugs against this disease have been reported in the literature [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. This is due to the fact that Variola virus strains may have been stored in clandestine sites around the world, and their potential use for bioterrorist purposes cannot be ignored [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico Studies of Potential Selective Inhibitors of Thymidylate Kinase from Variola virus

et al. 2021

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Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.

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Virtual screening, docking, and dynamics of potential new inhibitors of dihydrofolate reductase from Yersinia pestis

Cited by 15 publications

References 46 publications

Molecular Modeling Study of Uncharged Oximes Compared to HI-6 and 2-PAM Inside Human AChE Sarin and VX Conjugates

Molecular Modeling Study of Uncharged Oximes Compared to HI-6 and 2-PAM Inside Human AChE Sarin and VX Conjugates

Probing the origin of dihydrofolate reductase inhibition via proteochemometric modeling

In Silico Studies of Potential Selective Inhibitors of Thymidylate Kinase from Variola virus

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