Modeling and simulation study to identify threonine synthase as possible drug target in Leishmania major

Meshram, Rohan J.; Bagul, Kamini T; Aouti, Snehal; Shirsath, Akshay M; Duggal, Harleen; Gacche, Rajesh N.

doi:10.1007/s11030-020-10129-8

Cited by 8 publications

(3 citation statements)

References 113 publications

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“…Overall, the most stable model was SwissModel_2, followed by Mult1_lr and Mult1_lig. One possible explanation for the low stability of the Mult1_lig model would be that the model was built with an existing ligand that contributed to its stability and the protein was more flexible or disordered without it, as described in other previous studies [ 34 , 35 ]. In addition, our study showed that the average RMSD values corresponding to Lmj_04_BRCT models were similar to those reported for other BRCT domains ranging 3–4 Å [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Virtual screening was also performed with Glide XP, similarly to the docking experiments, and Epik state penalties were not used. The top 0.01% scoring interactions ( n = 300 compounds) were manually inspected and filtered according to the following criteria: Presence among the other top scoring models (the same compound is highly ranked among several homology models), the presence of at least two non-hydrophobic protein–ligand interactions, and noncovalent interactions through π electron-rich groups, as they provide significant stability and selectivity to the compounds [ 34 , 89 ].…”

Section: Methodsmentioning

confidence: 99%

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Discovery and Validation of Lmj_04_BRCT Domain, a Novel Therapeutic Target: Identification of Candidate Drugs for Leishmaniasis

Peña-Guerrero

Fernández-Rubio

Burguete-Mikeo

et al. 2021

IJMS

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Since many of the currently available antileishmanial treatments exhibit toxicity, low effectiveness, and resistance, search and validation of new therapeutic targets allowing the development of innovative drugs have become a worldwide priority. This work presents a structure-based drug discovery strategy to validate the Lmj_04_BRCT domain as a novel therapeutic target in Leishmania spp. The structure of this domain was explored using homology modeling, virtual screening, and molecular dynamics studies. Candidate compounds were validated in vitro using promastigotes of Leishmania major, L. amazonensis, and L. infantum, as well as primary mouse macrophages infected with L. major. The novel inhibitor CPE2 emerged as the most active of a group of compounds against Leishmania, being able to significantly reduce the viability of promastigotes. CPE2 was also active against the intracellular forms of the parasites and significantly reduced parasite burden in murine macrophages without exhibiting toxicity in host cells. Furthermore, L. major promastigotes treated with CPE2 showed significant lower expression levels of several genes (α-tubulin, Cyclin CYCA, and Yip1) related to proliferation and treatment resistance. Our in silico and in vitro studies suggest that the Lmj_04_BRCT domain and its here disclosed inhibitors are new potential therapeutic options against leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Discovery and Validation of Lmj_04_BRCT Domain, a Novel Therapeutic Target: Identification of Candidate Drugs for Leishmaniasis

Peña-Guerrero

Fernández-Rubio

Burguete-Mikeo

et al. 2021

IJMS

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“…Furthermore, antidepressants like sertraline have been evaluated and shown significant leishmanicidal action with a multi-target mechanism of action [ 67 ]. In silico studies have identified several drugs, including rifabutin, lamivudine, and metformin, as having the potential to eradicate the Leishmania parasite [ 68 , 69 , 70 ].…”

Section: Resultsmentioning

confidence: 99%

Overview of Research on Leishmaniasis in Africa: Current Status, Diagnosis, Therapeutics, and Recent Advances Using By-Products of the Sargassaceae Family

Abdoul-Latif,

Oumaskour,

Abdallah

et al. 2024

Pharmaceuticals

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Leishmaniasis in Africa, which has been designated as a priority neglected tropical disease by various global organizations, exerts its impact on millions of individuals, primarily concentrated within this particular region of the world. As a result of the progressively grave epidemiological data, numerous governmental sectors and civil organizations have concentrated their endeavors on this widespread outbreak with the objective of devising appropriate remedies. This comprehensive examination delves into multiple facets of this parasitic ailment, scrutinizing the associated perils, diagnostic intricacies, and deficiencies within the existing therapeutic protocols. Despite the established efficacy of current treatments, they are not immune to deleterious incidents, particularly concerning toxicity and the emergence of parasitic resistance, thus accentuating the necessity of exploring alternative avenues. Consequently, this research not only encompasses conventional therapeutic approaches, but also extends its scope to encompass complementary and alternative medicinal techniques, thereby striving to identify innovative solutions. A particularly auspicious dimension of this study lies in the exploration of natural substances and by-products derived from some brown algae of the Sargassaceae family. These resources possess the potential to assume a pivotal role in the management of leishmaniasis.

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Identification of potential inhibitors of coronavirus hemagglutinin-esterase using molecular docking, molecular dynamics simulation and binding free energy calculation

et al. 2020

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The pandemic outbreak of the Corona viral infection has become a critical global health issue. Biophysical and structural evidence shows that spike protein possesses a high binding affinity towards host angiotensin-converting enzyme 2 and viral hemagglutinin-acetylesterase (HE) glycoprotein receptor. We selected HE as a target in this study to identify potential inhibitors using a combination of various computational approaches such as molecular docking, ADMET analysis, dynamics simulations and binding free energy calculations. Virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin as potential HE inhibitors with better binding energy. Furthermore, molecular dynamics simulations for 100 ns time scale revealed that most of the key HE contacts were retained throughout the simulations trajectories. Binding free energy calculations using MM/PBSA approach ranked the top-five potential NPACT compounds which can act as effective HE inhibitors.

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Modeling and simulation study to identify threonine synthase as possible drug target in Leishmania major

Cited by 8 publications

References 113 publications

Discovery and Validation of Lmj_04_BRCT Domain, a Novel Therapeutic Target: Identification of Candidate Drugs for Leishmaniasis

Discovery and Validation of Lmj_04_BRCT Domain, a Novel Therapeutic Target: Identification of Candidate Drugs for Leishmaniasis

Overview of Research on Leishmaniasis in Africa: Current Status, Diagnosis, Therapeutics, and Recent Advances Using By-Products of the Sargassaceae Family

Identification of potential inhibitors of coronavirus hemagglutinin-esterase using molecular docking, molecular dynamics simulation and binding free energy calculation

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