Search for acrylonitrile-based inhibitors of SAR-Cov-19 main and papain-like proteases through covalent docking and high-throughput virtual screening
- Authors: Ntantiso, Yamkela
- Date: 2024-10-11
- Subjects: COVID-19 (Disease) , Acrylonitrile , Drug targeting , ZINC database , Covalent bond , Noncovalent bonding , Molecular dynamics simulation
- Language: English
- Type: Academic theses , Master's theses , text
- Identifier: http://hdl.handle.net/10962/463941 , vital:76459
- Description: The sudden outbreak of SARS-CoV-2 formerly known as the 2019 novel coronavirus (2019-nCoV) quickly turned into a pandemic of coronavirus disease 2019 (COVID-19), the scale of which has never been seen before. High infection rates and mortality from COVID-19 placed pressure on global health services, and this has been to the detriment of the global economy. However, treatment options for COVID-19 are still very limited; hence, it is now as important as ever that researchers explore searching for new compounds with pharmacokinetic properties that inhibit the two COVID proteases - the main protease (Mpro) and the papain-like protease (PLpro). The main protease is a cysteine protease; as such, it is susceptible to permanent inhibition by reactive species (warheads) that may covalently bind to cysteine residues. One such class of compounds is acrylonitriles, in which the reactive acrylonitrile is reactive towards cysteine through a Michael addition reaction. The resulting covalent interaction is permanent and inactivates the cysteine residue and hence the protease within the context of the COVID-19 life-cycle. In this context, this study seeks to utilize computational-based approaches to identify acrylonitrile-based inhibitors of coronavirus drug targets. To do this, the ZINC database has been screened for compounds containing acrylonitrile functionality, due to its known nature as a warhead that binds to cysteine residues. Pharmacokinetic properties are computed to evaluate the viability of identified inhibitors, and covalent and non-covalent molecular docking approaches to the Mpro enzyme crystal structure have also been used to assess the identified systems. To gather more information and evaluate the most promising systems, a subset of the most promising compounds have been subjected to molecular dynamics simulation (for both covalently bound and non-covalently bound systems). , Thesis (MSc) -- Faculty of Science, Biochemistry, Microbiology & Bioinformatics, 2024
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- Date Issued: 2024-10-11
Cyclooxygenase-1 as an anti-stroke target: potential inhibitor identification and non-synonymous single nucleotide polymorphism analysis
- Authors: Muronzi, Tendai
- Date: 2020
- Subjects: Cerebrovascular disease , Cerebrovascular disease -- Treatment , Cerebrovascular disease -- Chemotherapy , Cyclooxygenases , High throughput screening (Drug development) , Drug development , Molecular dynamics , South African Natural Compounds Database , ZINC database
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/143404 , vital:38243
- Description: Stroke is the third leading cause of death worldwide, with 87% of cases being ischemic stroke. The two primary therapeutic strategies to reduce post-ischemic brain damage are cellular and vascular approaches. The vascular strategy aims to rapidly re-open obstructed blood vessels, while the cellular approach aims to interfere with the signalling pathways that facilitate neuron damage and death. Unfortunately, popular vascular treatments have adverse side effects, necessitating the need for alternative chemotherapeutics. In this study, cyclooxygenase-1 (COX-1), which plays a significant role in the post- ischemic neuroinflammation and neuronal death, was targeted for identification of novel drug compounds and to assess the effect of nsSNPs on its structure and function. In a drug discovery part, ligands from the South African Natural Compounds Database (SANCDB-https://sancdb.rubi.ru.ac.za/) and ZINC database (http://zinc15.docking.org/) were used for high-throughput virtual screening (HVTS) against COX-1. Additionally, five nsSNPs were being investigated to assess their impact on protein structure and function. Three of these SNPs were in the COX-1 dimer interface. Molecular docking and molecular dynamics simulations revealed asymmetric nature of the protein. Several ligands, peculiar to each monomer, exhibited favourable binding energies in the respective active sites. SNP analysis indicated effects on inter-monomer interactions and protein stability.
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- Date Issued: 2020