Potential colchicine binding site inhibitors unraveled by virtual screening, molecular dynamics and MM/PBSA

Federico, Leonardo Bruno; Silva, Guilherme Martins; Gomes, Suzane Quintana; Francischini, Isaque Antônio Galindo; Barcelos, Mariana Pegrucci; Santos, Cleydson Breno Rodrigues dos; Costa, Luciano T.; Rosa, Joaquín M. Campos; Silva, Carlos Henrique Tomich de Paula da

doi:10.1016/j.compbiomed.2021.104817

Cited by 14 publications

(6 citation statements)

References 37 publications

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“…Ligand-based drug designing is one of the Insilco-based methods that aid in establishing a quantitative relationship between the structures of inhibitors and their inhibitory activities [13]. The quantitative structure and activity relationship (QSAR) approach attempts at identifying and quantify the relationship between molecular structures and certain Physico-chemical properties.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: In-silico discovery of novel microtubule inhibitors targeting colchicine binding site; A combined Group-based QSAR approach

Sahu

Ojha

2022

Preprint

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Microtubules are a potential target for the design and development of novel anti-mitotic drugs for cancer therapy Focusing on their mechanisms of action, Microtubuletargeting agents are classified into stabilizers and destabilizers, among them destabilizers binding to colchicine binding site domain is an important source of research in recent years. A number of molecules containing indole scaffold have been described as tubulin polymerization inhibitors with the potential to interact with the colchicine binding site. The research is focused on the search for new indole-based colchicine binding site inhibitors, for that fragment-based QSAR utilized for the important interacting site for potent fragment attachment and the designed fragment library screened for the finding of the potent molecule and finally, three molecules screened and validated for their reactivity using DFT and stability using Molecular dynamics simulation, among them m16 showing the potential result with high interaction energy, high molecular reactivity and confirms high stability as compared to others.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: In-silico discovery of novel microtubule inhibitors targeting colchicine binding site; A combined Group-based QSAR approach

Sahu

Ojha

2022

Preprint

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“…After using ROCS, compounds were filtered using the EON electrostatic potential similarity between them and the same query, resulting in 17,000 compounds. This combination of methodologies (i.e., shape-and electrostatic-filtering) has also achieved successful results, as reported in the literature ( [71][72][73]).…”

Section: Virtual Screening Using Workflowsupporting

confidence: 60%

Discovery of Potential GSK-3β Allosteric Modulators for Alzheimer’s Disease

Silva

Alves

Gomes

et al. 2023

Preprint

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Glycogen Synthase Kinase-3 beta (GSK-3β) is a validated target-enzyme associated with Alzheimer’s Disease (AD). Usage of allosteric inhibitors of this enzyme represents a valid and promising therapeutic strategy due to their selective and subtle modulation, with a low probability of producing side effects. Nonetheless, only a few GSK-3β allosteric modulators with limited binding affinity have been uncovered so far and published in the public domain. Previous Virtual Screening (VS) studies have not considered such mechanism of action and did not achieve chemical diversity. Therefore, we applied two orthogonal VS workflows by means of shape-based similarity, QSAR, docking, and ADMET filters to select new and diverse GSK-3β allosteric inhibitors. Obtained hits have shown enhanced structural diversity and preliminary results as GSK-3β allosteric inhibitors according to in vitro assays. Furthermore, their GSK-3β allosteric inhibition were analyzed by blind docking and pocket coverage studies. These hits can be employed as template molecules for the discovery of more potent inhibitors, with the aim to expand the chemical space of GSK-3β allosteric modulators as promising agents in AD.

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“…In addition, the best stability in MD simulations and great Δ G bind through MM-PBSA calculations (−103.13 KJ/mol) propose the CPBLa as a possible drug target. Others works highlight these methods as essential to predict drug targets of leishmaniasis [ 76 , 77 ]. Furthermore, these findings are in agreement with other works that underline the acridine derivatives as promising cysteine protease inhibitors [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation

et al. 2023

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The present study proposed the synthesis of a novel acridine derivative not yet described in the literature, chemical characterization by NMR, MS, and IR, followed by investigations of its antileishmanial potential. In vitro assays were performed to assess its antileishmanial activity against L. amazonensis strains and cytotoxicity against macrophages through MTT assay and annexin V-FITC/PI, and the ability to perform an immunomodulatory action using CBA. To investigate possible molecular targets, its interaction with DNA in vitro and in silico targets were evaluated. As results, the compound showed good antileishmanial activity, with IC50 of 6.57 (amastigotes) and 94.97 (promastigotes) µg mL−1, associated with non-cytotoxicity to macrophages (CC50 > 256.00 µg mL−1). When assessed by flow cytometry, 99.8% of macrophages remained viable. The compound induced an antileishmanial effect in infected macrophages and altered TNF-α, IL-10 and IL-6 expression, suggesting a slight immunomodulatory activity. DNA assay showed an interaction with the minor grooves due to the hyperchromic effect of 47.53% and Kb 1.17 × 106 M−1, and was sustained by docking studies. Molecular dynamics simulations and MM-PBSA calculations propose cysteine protease B as a possible target. Therefore, this study demonstrates that the new compound is a promising molecule and contributes as a model for future works.

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Potential colchicine binding site inhibitors unraveled by virtual screening, molecular dynamics and MM/PBSA

Cited by 14 publications

References 37 publications

WITHDRAWN: In-silico discovery of novel microtubule inhibitors targeting colchicine binding site; A combined Group-based QSAR approach

WITHDRAWN: In-silico discovery of novel microtubule inhibitors targeting colchicine binding site; A combined Group-based QSAR approach

Discovery of Potential GSK-3β Allosteric Modulators for Alzheimer’s Disease

ACW-02 an Acridine Triazolidine Derivative Presents Antileishmanial Activity Mediated by DNA Interaction and Immunomodulation

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