Computer-aided drug design: time to play with novel chemical matter

Barril, Xavier

doi:10.1080/17460441.2017.1362386

Cited by 14 publications

(5 citation statements)

References 30 publications

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“…It is worth noting that there are some well-established computational methods for hotspot searching, such as FTMap , and cosolvent molecular dynamics simulation. − FTMap docks small molecular probes onto the target protein to identify the druggable hotspots on the surface efficiently. The cosolvent molecular dynamics, which shares the similar fundamental principles, could simulate the protein system with the probes, allowing one to identify the potential drug binding pockets in a dynamic manner.…”

Section: Resultsmentioning

confidence: 99%

Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein–Protein Interaction

Guo

Yan

et al. 2023

J. Chem. Inf. Model.

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Protein–protein interactions (PPIs), in general, are attractive yet challenging drug targets. As a typical PPI, MTDH-SND1 interaction has recently been reported to be a promising drug target to malignant breast cancer and other cancer types. However, the lack of well-defined deep pockets on the MTDH-SND1 interface makes it a tough target for rational drug discovery attempts. To address this issue, in this study, a long time-scale molecular dynamics (MD) simulation-driven focused screening strategy was proposed and reported. A total of 12 virtual hits were purchased and tested in SPR assay, yielding 10 SND1 binders with micromolar or less affinities. As an example, compound L5, the second best hit with a K D of 2.64 μM, was further assayed in MDA-MB-231 breast cancer cells, showing an antiproliferation IC50 value of 57 μM in a CCK8 assay with a dampened interruption between MTDH and SND1 proteins detected by immunofluorescence colocalization imaging. As the most potent small molecule inhibitor in the class so far, our preliminary study combining molecular dynamics simulation and in vitro cellular functional evidence indicates L5 could serve as a lead compound for future optimization or pharmacologic studies, and the MD-driven focused screening strategy could be useful for other PPI drug discovery attempts.

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Section: Resultsmentioning

confidence: 99%

Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein–Protein Interaction

Guo

Yan

et al. 2023

J. Chem. Inf. Model.

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“…The low procurement rate also forced us to introduce a synthetic step to obtain compound 23 , which is less efficient and involves human bias in compound selection (synthetic feasibility). However, the platform is not tied to any particular database, and future implementations will explore alternative compound sources including much larger on-demand collections. , A very low false positive rate is essential, particularly when using the platform for fragment growth, because each iteration relies on the predictions obtained for the previous one. A high proportion of spurious hits would result in rapid performance decay.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space

et al. 2021

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Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD.

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“…Computational methods play a substantial role in the drug discovery process [40]. Homology modeling and molecular docking are among the computational methods that enable the drug discovery process faster, cheaper and more efficient.…”

Section: Introductionmentioning

confidence: 99%

Fluorescence labelled XT5 modified nano-capsules enable highly sensitive myeloma cells detection

Dizaji¹,

Kohneshahri²,

Gafil³

et al. 2022

Nanotechnology

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Accurate diagnosis of cancer cells in early stages plays an important role in reliable therapeutic strategies. In this study, we aimed to develop fluorescence-conjugated polymer carrying nanocapsules (NCs) which is highly selective for myeloma cancer cells. To gain specific targeting properties, NCs, XT5 molecules (a benzamide derivative) which shows high affinity properties against protease-activated receptor-1 (PAR1), that overexpressed in myeloma cancer cells, was used. For this purpose, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000]-carboxylic acid (DSPE-PEG2000-COOH) molecules, as a main encapsulation material, was conjugated to XT5 molecules due to esterification reaction using N,N'-dicyclohexylcarbodiimide (DCC) as a coupling agent. The synthesized DSPE-PEG2000-COO-XT5 was characterized by using FT-IR and 1H NMR spectroscopies and results indicated that XT5 molecules were successfully conjugated to DSPE-PEG2000-COOH. Poly(fluorene-alt-benzothiadiazole) (PFBT) conjugated polymer was encapsulated with DSPE-PEG2000-COO-XT5 due to dissolving in THF and ultra-sonication in an aqueous solution, respectively. The morphological properties, UV-vis absorbance, and emission properties of obtained conjugated polymer encapsulated DSPE-PEG2000-COO-XT5 (CPDP-XT5) NCs was determined by utilizing scanning electron microscopy (SEM), UV-vis spectroscopy, and fluorescent spectroscopy, respectively. Cytotoxicity properties of CPDP-XT5 was evaluated by performing MTT assay on RPMI 8226 myeloma cell lines. Cell viability results confirmed that XT5 molecules were successfully conjugated to DSPE-PEG2000-COOH. Specific targeting properties of CPDP-XT5 NCs and XT5-free NCs (CPDP NCs) were investigated on RPMI 8226 myeloma cell lines by utilizing fluorescent microscopy and results indicated that CPDP-XT5 NCs shows significantly high affinity in comparison to CPDP NCs against the cells. Homology modeling and molecular docking properties of XT5 molecules were evaluated and simulation results confirmed our results.

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Computer-aided drug design: time to play with novel chemical matter

Cited by 14 publications

References 30 publications

Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein–Protein Interaction

Molecular Dynamics Simulation-Driven Focused Virtual Screening and Experimental Validation of Inhibitors for MTDH-SND1 Protein–Protein Interaction

Discovery of Novel BRD4 Ligand Scaffolds by Automated Navigation of the Fragment Chemical Space

Fluorescence labelled XT5 modified nano-capsules enable highly sensitive myeloma cells detection

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