The Pharmacophore Concept and Its Applications in Computer-Aided Drug Design

Seidel, Thomas; Schuetz, Doris A.; Garon, Arthur; Langer, Thierry

doi:10.1007/978-3-030-14632-0_4

Cited by 49 publications

(41 citation statements)

References 105 publications

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“…Over the last decade, computer aided drug discovery has emerged as a fundamental tool in drug discovery and design process [45][46][47][48]. Identification of compounds that bind and inhibit normal function of proteins involved in viral replication has been the most successful strategy in direct acting antiviral drug discovery [49][50][51][52].…”

Section: Discussionmentioning

confidence: 99%

Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach

Iftikhar

Ali

Farooq

et al. 2020

Computers in Biology and Medicine

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The recent outbreak of coronavirus disease-19 (COVID-19) continues to drastically affect healthcare throughout the world. To date, no approved treatment regimen or vaccine is available to effectively attenuate or prevent the infection. Therefore, collective and multidisciplinary efforts are needed to identify new therapeutics or to explore effectiveness of existing drugs and drug-like small molecules against SARS-CoV-2 for lead identification and repurposing prospects. This study addresses the identification of small molecules that specifically bind to any of the three essential proteins (RdRp, 3CL-protease and helicase) of SARS-CoV-2. By applying computational approaches we screened a library of 4574 compounds also containing FDA-approved drugs against these viral proteins. Shortlisted hits from initial screening were subjected to iterative docking with the respective proteins. Ranking score on the basis of binding energy, clustering score, shape complementarity and functional significance of the binding pocket was applied to identify the binding compounds. Finally, to minimize chances of false positives, we performed docking of the identified molecules with 100 irrelevant proteins of diverse classes thereby ruling out the non-specific binding. Three FDA-approved drugs showed binding to 3CL-protease either at the catalytic pocket or at an allosteric site related to functionally important dimer formation. A drug-like molecule showed binding to RdRp in its catalytic pocket blocking the key catalytic residues. Two other druglike molecules showed specific interactions with helicase at a key domain involved in catalysis. This study provides lead drugs or drug-like molecules for further in vitro and clinical investigation for drug repurposing and new drug development prospects.

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Section: Discussionmentioning

confidence: 99%

Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach

Iftikhar

Ali

Farooq

et al. 2020

Computers in Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…Starting by the experimental structure of a protein-ligand complex, it is possible to investigate by computational tools the structural features that other potential ligands should have, in order to be able to bind the protein. This procedure is known as the creation of a pharmacophore model, and it is followed by virtual screening, i.e., the search of a large data set of molecules in order to find candidate ligands that fit with the pharmacophore model [23]. Further computational studies can verify how the ligands may interact with the protein, as in the case of docking simulations [24].…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening of Natural Compounds as Potential PI3K-AKT1 Signaling Pathway Inhibitors and Experimental Validation

et al. 2021

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A computational screening for natural compounds suitable to bind the AKT protein has been performed after the generation of a pharmacophore model based on the experimental structure of AKT1 complexed with IQO, a well-known inhibitor. The compounds resulted as being most suitable from the screening have been further investigated by molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis and toxicity profiles. Two compounds selected at the end of the computational analysis, i.e., ZINC2429155 (also named STL1) and ZINC1447881 (also named AC1), have been tested in an experimental assay, together with IQO as a positive control and quercetin as a negative control. Only STL1 clearly inhibited AKT activation negatively modulating the PI3K/AKT pathway.

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“…Properties such as the molecular hydrophobicity parameter LogP, molecular weight (MW) and the total polar surface area (TPSA) have been broadly used in modern rational drug discovery and design 46 . The MW of the top 10 compounds (L5RF7, L5RFL, L5R7Z, L5REN, L5RFJ, L5REX, L5RFQ, L5RFW, L5RFA, L5RFE; Figure 2 ) varies in a short range from 209.24 to 268.35 g/mol.…”

Section: Resultsmentioning

confidence: 99%

COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor

Feitosa¹,

Júnior²,

Neto³

et al. 2020

Int. J. Med. Sci.

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The SARS-CoV-2 spread quickly across the globe. The World Health Organization (WHO) on March 11 declared COVID-19 a pandemic. The mortality rate, hospital disorders and incalculable economic and social damages, besides the unproven efficacy of the treatments evaluated against COVID-19, raised the need for immediate control of this disease. Therefore, the current study employed in silico tools to rationally identify new possible SARS-CoV-2 main protease (Mpro) inhibitors. That is an enzyme conserved among the coronavirus species; hence, the identification of an Mpro inhibitor is to make it a broad-spectrum drug. Molecular docking studies described the binding sites and the interaction energies of 74 Mpro-ligand complexes deposited in the Protein Data Bank (PDB). A structural similarity screening was carried out in order to identify possible Mpro ligands that show additional pharmacological properties against COVID-19. We identified 59 hit compounds and among them, melatonin stood out due to its prominent immunomodulatory and anti-inflammatory activities; it can reduce oxidative stress, defence cell mobility and efficiently combat the cytokine storm and sepsis. In addition, melatonin is an inhibitor of calmodulin, an essential intracellular component to maintain angiotensin-converting enzyme 2 (ACE-2) on the cell surface. Interestingly, one of the most promising hits in our docking study was melatonin. It revealed better interaction energy with Mpro compared to ligands in complexes from PDB. Consequently, melatonin can have response potential in early stages for its possible effects on ACE-2 and Mpro, although it is also promising in more severe stages of the disease for its action against hyper-inflammation. These results definitely do not confirm antiviral activity, but can rather be used as a basis for further preclinical and clinical trials.

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The Pharmacophore Concept and Its Applications in Computer-Aided Drug Design

Cited by 49 publications

References 105 publications

Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach

Identification of potential inhibitors of three key enzymes of SARS-CoV2 using computational approach

Virtual Screening of Natural Compounds as Potential PI3K-AKT1 Signaling Pathway Inhibitors and Experimental Validation

COVID-19: Rational discovery of the therapeutic potential of Melatonin as a SARS-CoV-2 main Protease Inhibitor

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