MANORAA: A machine learning platform to guide protein-ligand design by anchors and influential distances

Tanramluk, Duangrudee; Pakotiprapha, Danaya; Phoochaijaroen, Sakao; Chantravisut, Pattra; Thampradid, Sirikanya; Vanichtanankul, Jarunee; Narupiyakul, Lalita; Akavipat, Ruj; Yuvaniyama, Jirundon

doi:10.1016/j.str.2021.09.004

Cited by 5 publications

(4 citation statements)

References 40 publications

(55 reference statements)

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“…As can be seen from the rediscovery of these aforementioned residues, SIMFONEE can be used to confirm or discover crucial binding atoms computationally. Importantly, it can be used to predict the anchoring points for drug inhibitor design according to our previous work 16 .…”

Section: Resultsmentioning

confidence: 99%

“…The superposition of both SARS-CoV and SARS-CoV-2 M pro is used to determine the frequently occurring atoms of M pro from various Coronavirus species. Although, these frequently occurring atoms may not interact directly with the drug molecule, our previous studies showed that they can be used as anchoring points for measuring the influential distances that can guide ligand design 16 , 17 . Then, the structures of M pro SARS-CoV-2 are analysed to show the parts that are position-specific via our 4-dimensional grid analysis.…”

Section: Introductionmentioning

confidence: 99%

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Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Rungruangmaitree

Phoochaijaroen

Chimprasit

et al. 2023

Sci Rep

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With the rapid rate of SARS-CoV-2 Main protease (Mpro) structures deposition, a computational method that can combine all the useful structural features becomes crucial. This research focuses on the frequently occurring atoms and residues to find a generalized strategy for inhibitor design given a large amount of protein complexes from SARS-CoV in contrast to SARS-CoV-2 Mpro. By superposing large numbers of the ligands onto the protein template and grid box, we can analyse which part of the structure is conserved from position-specific interaction for both data sets for the development of pan-Mpro antiviral design. The difference in conserved recognition sites from the crystal structures can be used to determine specificity determining residues for designing selective drugs. We can display pictures of the imaginary shape of the ligand by unionising all atoms from the ligand. We also pinpoint the most probable atom adjustments to imitate the frequently found densities from the ligand atoms statistics. With molecular docking, Molecular Dynamics simulation, and MM-PBSA methods, a carbonyl replacement at the nitrile warhead (N5) of Paxlovid’s Nirmatrelvir (PF-07321332) was suggested. By gaining insights into the selectivity and promiscuity regions for proteins and ligands, crucial residues are highlighted, and the antiviral design strategies are proposed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Rungruangmaitree

Phoochaijaroen

Chimprasit

et al. 2023

Sci Rep

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“…Machine learning further boosts drug design. Here, an algorithm searches for general structural patterns of desired pharmacodynamical and/or pharmacokinetic properties in known molecules and tries to transfer these properties into structures of newly designed compounds ( Graff et al, 2021 ; Priya et al, 2022 ; Tanramluk et al, 2022 ; Zhang and Lee, 2019 ; Zhang et al, 2022 ). All the artificial intelligence (AI) approaches need experimental data sets for a starting input as well as for validation (e.g., X-ray structures, inhibition constants).…”

Section: Sars-cov-2 and Antiviral Therapymentioning

confidence: 99%

Viral proteases as therapeutic targets

Majerová

Konvalinka

2022

Molecular Aspects of Medicine

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“…The CFTR structure obtained from electron cryomicroscopy (cryo-EM) was used as a reference molecule (Protein Data Bank ID: 5UAK.pdb; [18]), and all possible pockets were identified using PrankWeb [19]. The MANORAA platform was used to sketch and obtain proteinligand interacting motifs based on the three-dimensional coordinates from the Protein Data Bank (PDB) [20]. HyperChem was used to correct bond order and hydrogen atoms of the ligand CFTR inh -172 and genistein.…”

Section: In Silico Analysis Of Cftr Inh -172 and Genistein Bindingmentioning

confidence: 99%

Vasoactive intestinal peptide and cystic fibrosis transmembrane conductance regulator contribute to the transepithelial calcium transport across intestinal epithelium-like Caco-2 monolayer

et al. 2022

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Vasoactive intestinal peptide (VIP) as a neurocrine factor released by enteric neurons has been postulated to participate in the regulation of transcellular active calcium transport across intestinal epithelium, but the preceding evidence is scant and inconclusive. Herein, transepithelial calcium flux and epithelial electrical parameters were determined by Ussing chamber technique with radioactive tracer in the intestinal epithelium-like Caco-2 monolayer grown on Snapwell. After 3-day culture, Caco-2 cells expressed mRNA of calcium transporters, i.e., TRPV6, calbindin-D9k, PMCA1b and NCX1, and exhibited transepithelial resistance of ~200 Ω cm2, a characteristic of leaky epithelium similar to the small intestine. VIP receptor agonist was able to enhance transcellular calcium flux, whereas VIP receptor antagonist totally abolished calcium fluxes induced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Since the intestinal cystic fibrosis transmembrane conductance regulator (CFTR) could be activated by VIP and calciotropic hormones, particularly parathyroid hormone, we sought to determine whether CFTR also contributed to the 1,25(OH)2D3-induced calcium transport. A selective CFTR inhibitor (20–200 μM CFTRinh-172) appeared to diminish calcium fluxes as well as transepithelial potential difference and short-circuit current, both of which indicated a decrease in electrogenic ion transport. On the other hand, 50 μM genistein—a molecule that could rapidly activate CFTR—was found to increase calcium transport. Our in silico molecular docking analysis confirmed direct binding of CFTRinh-172 and genistein to CFTR channels. In conclusion, VIP and CFTR apparently contributed to the intestinal calcium transport, especially in the presence of 1,25(OH)2D3, thereby supporting the existence of the neurocrine control of intestinal calcium absorption.

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MANORAA: A machine learning platform to guide protein-ligand design by anchors and influential distances

Cited by 5 publications

References 40 publications

Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors

Viral proteases as therapeutic targets

Vasoactive intestinal peptide and cystic fibrosis transmembrane conductance regulator contribute to the transepithelial calcium transport across intestinal epithelium-like Caco-2 monolayer

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