The implementation of RAAF in the OECD QSAR Toolbox

Kuseva, Chanita; Schultz, T.W.; Yordanova, Darina; Tankova, Ksenia; Kutsarova, Stela; Pavlov, Todor; Chapkanov, Atanas; Georgiev, Мarin; Gissi, Andrea; Sobański, Tomasz; Mekenyan, Ovanes G.

doi:10.1016/j.yrtph.2019.03.018

Cited by 22 publications

(12 citation statements)

References 7 publications

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“…In this connection, before biochemical assays, these compounds should go through a lead optimization, iterative process of altering the molecule structure to identify their chemical modifications with improved antiviral potency and ADMET parameters. For this purpose, the modern QSAR methods commonly used as a lead optimization approach in drug discovery may be applied (Golbraikh et al., 2017 ; Kuseva et al., 2019 ; Schultz et al., 2018 ).…”

Section: Resultsmentioning

confidence: 99%

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Computational discovery of small drug-like compounds as potential inhibitors of SARS-CoV-2 main protease

Andrianov

Kornoushenko

Karpenko

et al. 2020

Journal of Biomolecular Structure and Dynamics

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A computational approach to in silico drug discovery was carried out to identify small drug-like compounds able to show structural and functional mimicry of the high affinity ligand X77, potent non-covalent inhibitor of SARS-COV-2 main protease (M Pro ). In doing so, the X77-mimetic candidates were predicted based on the crystal X77-M Pro structure by a public web-oriented virtual screening platform Pharmit. Models of these candidates bound to SARS-COV-2 M Pro were generated by molecular docking, quantum chemical calculations and molecular dynamics simulations. At the final point, analysis of the interaction modes of the identified compounds with M Pro and prediction of their binding affinity were carried out. Calculation revealed 5 top-ranking compounds that exhibited a high affinity to the active site of SARS-CoV-2 M Pro . Insights into the ligand − M Pro models indicate that all identified compounds may effectively block the binding pocket of SARS-CoV-2 M Pro , in line with the low values of binding free energy and dissociation constant. Mechanism of binding of these compounds to M Pro is mainly provided by van der Waals interactions with the functionally important residues of the enzyme, such as His-41, Met-49, Cys-145, Met-165, and Gln-189 that play a role of the binding hot spots assisting the predicted molecules to effectively interact with the M Pro active site. The data obtained show that the identified X77-mimetic candidates may serve as good scaffolds for the design of novel antiviral agents able to target the active site of SARS-CoV-2 M Pro . Communicated by Ramaswamy H. Sarma

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Section: Resultsmentioning

confidence: 99%

“…identify their chemical modifications with improved antiviral potency and ADMET parameters. For this purpose, the modern QSAR methods commonly used as a lead optimization approach in drug discovery may be applied (Golbraikh et al, 2017;Kuseva et al, 2019;Schultz et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Computational discovery of small drug-like compounds as potential inhibitors of SARS-CoV-2 main protease

Andrianov

Kornoushenko

Karpenko

et al. 2020

Journal of Biomolecular Structure and Dynamics

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“…Retrieved analogues were structured into a coherent framework based on read-across assessment framework (RAAF) [42] generated as summarized report, categorical report and data matrix. We evaluated the cytotoxic and mutagenic potential of the target chemical by analyzing the following target endpoint: skin sensitization (protein binding alerts for skin sensitization according to GSH and protein binding alerts for skin sensitization by OASIS profilers), oral and inhalation toxicity (toxic hazard classification by Cramer and organic functional groups profilers), mutagenicity (the mutagenic potential of DDVP based on DNA alerts for carcinogenicity and mutagenicity by OASIS profiler).…”

Section: Results Analysismentioning

confidence: 99%

Assessment of the cytotoxic and mutagenic potential of dichlorvos (DDVP) using in silico classification model; a health hazard awareness in Nigeria

Abaukaka

Sanusi

Abdullahi

et al. 2020

Environ Anal Health Toxicol

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Dichlorvos (DDVP) has been abused in Nigeria for suicide attempts, topical applications to treat an ectoparasitic infestation, and indiscriminate use on farm produce. Exposure to this compound in subacute concentration can cause toxicity in different tissues by alteration of the cellular antioxidative defence mechanism. This analysis is aimed at the systematic profiling of DDVP to assess its cytotoxic and mutagenic potential for human vulnerability using an in silico classification model. DDVP was grouped into categories of analogue chemical compounds generated from inventories based on structural alerts that measure the biological effects on cell lines and animal models using the quantitative structure-activity relationship (QSAR) model. The cytotoxic and mutagenic potential of DDVP was assessed by analyzing target endpoints like skin sensitization, oral/inhalation toxicity, neurotoxicity and mutagenicity. DDVP shows moderate sensitization potential that can induce skin irritation during prolonged exposure because of the presence of dichlorovenyl side-chain that interacts with cellular proteins and causes degradation. 50% lethal dose (LD 50 ) of DDVP per body weight was determined to be 26.2 mg/kg in a rat model at 95% confidence range for acute oral toxicity, and 14.4 mmol/L was estimated as 50% lethal concentration (LC 50 ) in the atmosphere due to acute inhalation toxicity. DDVP can also inhibit acetylcholinesterase in the nervous system to produce nicotinic and muscarinic symptoms like nausea, vomiting, lacrimation, salivation, bradycardia, and respiratory failure may cause death. The widely used pesticide causes weak DNA methylation which can repress gene transcription on promoter sites. DDVP is volatile so it can cause oral and inhalation toxicity coupled with neurotoxicity during prolonged exposure. Serum cholinesterase blood tests should be encouraged in federal and state hospitals to investigate related health challenges as DDVP is still used in Nigeria.

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“…1, 2) представляют значительный интерес для проведения дальнейших экспериментальных и теоретических исследований. Эти исследования включают химический синтез лигандов, биомедицинские испытания in vitro и оптимизацию структуры соединения-лидера методами QSAR [61,62], направленную на получение его аналогов с улучшенной противоопухолевой активностью и приемлемыми фармакокинетическими и токсикологическими параметрами.…”

Section: заключениеunclassified

Rational Design of Potential Bcr-Abl Tyrosine Kinase Inhibitors by the Methods of Molecular Modeling

Anrdrianov¹,

Kornoushenko²,

Karpenko³

et al. 2020

Math.Biol.Bioinf.

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Discovery of the nature of inhibiting cancer processes by small organic molecules has changed the principles of the development of drug compounds for antitumor therapy. Recent achievements in this area are associated with the design of small-molecule protein kinase inhibitors, organic compounds exhibiting directed pathogenetic action. In this study, in silico design of 38 potential anti-cancer compounds with multikinase profile was carried out based on the derivatives of 2-arylaminopyrimidine. Evaluation of inhibitory activity potential of these compounds against the native and mutant (T315I) forms of Bcr-Abl tyrosine kinase, an enzyme that plays a key role in the pathogenesis of chronic myeloid leukemia characterized by uncontrolled growth myeloid cells in peripheral blood and bone marrow, was performed using molecular modeling tools. As a result, 5 top-ranking compounds that exhibit, according to the calculated data, a high-affinity binding to the native and mutant Bcr-Abl tyrosine kinase were identified. The designed compounds were shown to form good scaffolds for the development of novel potent antitumor drugs.

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The implementation of RAAF in the OECD QSAR Toolbox

Cited by 22 publications

References 7 publications

Computational discovery of small drug-like compounds as potential inhibitors of SARS-CoV-2 main protease

Computational discovery of small drug-like compounds as potential inhibitors of SARS-CoV-2 main protease

Assessment of the cytotoxic and mutagenic potential of dichlorvos (DDVP) using in silico classification model; a health hazard awareness in Nigeria

Rational Design of Potential Bcr-Abl Tyrosine Kinase Inhibitors by the Methods of Molecular Modeling

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