Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

Saeed, Amir; Alam, Md. Jahoor; Alreshidi, Mousa

doi:10.3390/molecules26061549

Cited by 18 publications

(10 citation statements)

References 37 publications

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“…For peptidomimetic inhibitors, the chemical pharmacophores of N3 consisted of HBD with E166, Q189, and T190, HBA with E166, and hydrophobic interactions with T25, M49, M165, and A191, in correspondence to the previous reports of pharmacophore generated from the co-crystal structure (6LU7.pdb) [ 27 , 68 ]. Similar to N3, the 13b also had HBA with E166 and hydrophobic interactions with T25, L27, M49, and M165.…”

Section: Resultssupporting

confidence: 53%

“…Additionally, the phytochemical compounds retrieved from the PubChem database were screened considering the PHASE screen score, by which six lead compounds, 44256891, 44256921, 102452140, 131751762, 131831710, and 139031086, were obtained [ 26 ]. Five natural compounds with pharmacokinetic characteristics (daidzin, phloretin, rosmarinic acid, higenamine hydrochloride, and naringenin chalcone) were screened from the ZINC database using the LUDI-based pharmacophore model of N3, followed by a molecular docking study with MolDock [ 27 ]. The small-molecule inhibitors of 3CL pro, including rottlerin (37 μM), amentoflavone (143 μM), and baicalein (208 μM) with IC 50 in the micromolar range were identified using molecular docking and ligand-based screening [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening

et al. 2022

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SARS-CoV-2 causes the current global pandemic coronavirus disease 2019. Widely-available effective drugs could be a critical factor in halting the pandemic. The main protease (3CLpro) plays a vital role in viral replication; therefore, it is of great interest to find inhibitors for this enzyme. We applied the combination of virtual screening based on molecular docking derived from the crystal structure of the peptidomimetic inhibitors (N3, 13b, and 11a), and experimental verification revealed FDA-approved drugs that could inhibit the 3CLpro of SARS-CoV-2. Three drugs were selected using the binding energy criteria and subsequently performed the 3CLpro inhibition by enzyme-based assay. In addition, six common drugs were also chosen to study the 3CLpro inhibition. Among these compounds, lapatinib showed high efficiency of 3CLpro inhibition (IC50 value of 35 ± 1 μM and Ki of 23 ± 1 μM). The binding behavior of lapatinib against 3CLpro was elucidated by molecular dynamics simulations. This drug could well bind with 3CLpro residues in the five subsites S1’, S1, S2, S3, and S4. Moreover, lapatinib’s key chemical pharmacophore features toward SAR-CoV-2 3CLpro shared important HBD and HBA with potent peptidomimetic inhibitors. The rational design of lapatinib was subsequently carried out using the obtained results. Our discovery provides an effective repurposed drug and its newly designed analogs to inhibit SARS-CoV-2 3CLpro.

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Section: Resultssupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening

et al. 2022

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“…Tese targets could successfully dock with the active compositions of PB. Molecular docking is an efective method to verify the binding of natural compounds to the target proteins [49,50,85]. Te hydrophobic interaction and hydrogen bond interaction between compounds and amino acids of target proteins can promote stable binding [49,50,85].…”

Section: Discussionmentioning

confidence: 99%

Pharmacology Mechanism of Polygonum Bistorta in Treating Ulcerative Colitis Based on Network Pharmacology

Liu

Cao

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Aim. Ulcerative colitis (UC) is a refractory gastrointestinal disease. The study aimed to expound the mechanism of Polygonum bistorta (PB) in treating UC by network pharmacology, molecular docking, and experiment verification. Methods. The compositions and targets of PB and UC-associated targets were obtained by searching the websites and the literature. The potential mechanism of PB in the treatment of UC was predicted by protein-protein interaction network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Molecule docking was performed by AutoDock. In vitro experiments explored the mechanism of quercetin (Que), the main active composition of PB, in treating UC. Results. Six compositions, 139 PB targets, and 934 UC-associated targets were obtained. 93 overlapping targets between PB and UC were identified, and 18 of them were the core targets. 467 biological processes, 10 cell components, and 30 molecular functions were obtained by GO analysis. 102 pathways were enriched through KEGG analysis. Among them, the IL-17 signaling pathway had high importance. The core targets FOS, JUN, IL-1β, CCL2, CXCL8, and MMP9 could dock with Que successfully. Act1, TRAF6, FOS, and JUN were identified by KEGG as the key proteins of the IL-17 signaling pathway. The expressions of the abovementioned proteins were increased in Caco-2 cells stimulated by Dextran sulfate sodium and decreased after being treated by Que. Conclusion. PB might treat UC by downregulating the IL-17 signaling pathway. It is worth doing further research on PB treating UC in vivo.

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“…A 3D structure of the protein-inhibitor complex is often utilized to suggest novel substituents for an existing inhibitor. LUDI can link fragments to existing ligands and fit them into interaction sites [ 19 , 20 , 21 ].…”

Section: Materials and Methodologymentioning

confidence: 99%

Identification of Putative Plant-Based ALR-2 Inhibitors to Treat Diabetic Peripheral Neuropathy

Tasleem

Shoib

Kausar

et al. 2022

CIMB

Self Cite

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Diabetic peripheral neuropathy (DPN) is a common diabetes complication (DM). Aldose reductase -2 (ALR-2) is an oxidoreductase enzyme that is most extensively studied therapeutic target for diabetes-related complications that can be inhibited by epalrestat, which has severe adverse effects; hence the discovery of potent natural inhibitors is desired. In response, a pharmacophore model based on the properties of eplarestat was generated. The specified pharmacophore model searched the NuBBEDB database of natural compounds for prospective lead candidates. To assess the drug-likeness and ADMET profile of the compounds, a series of in silico filtering procedures were applied. The compounds were then put through molecular docking and interaction analysis. In comparison to the reference drug, four compounds showed increased binding affinity and demonstrated critical residue interactions with greater stability and specificity. As a result, we have identified four potent inhibitors: ZINC000002895847, ZINC000002566593, ZINC000012447255, and ZINC000065074786, that could be used as pharmacological niches to develop novel ALR-2 inhibitors.

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Receptor-Based Pharmacophore Modeling in the Search for Natural Products for COVID-19 Mpro

Cited by 18 publications

References 37 publications

Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening

Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening

Pharmacology Mechanism of Polygonum Bistorta in Treating Ulcerative Colitis Based on Network Pharmacology

Identification of Putative Plant-Based ALR-2 Inhibitors to Treat Diabetic Peripheral Neuropathy

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