scholarly journals Targeted Oxidation Strategy (TOS) for Potential Inhibition of Coronaviruses by Disulfiram — a 70-Year Old Anti-Alcoholism Drug

2020 ◽  
Author(s):  
Luyan Xu ◽  
Jiahui Tong ◽  
Yiran Wu ◽  
Suwen Zhao ◽  
Bo-Lin Lin
Keyword(s):  
Clinical Trial ◽  
New Drugs ◽  
Phase Iii ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
Phase Iii Clinical Trial ◽  
Drug Candidates ◽  
Thiol Proteases ◽  
Non Covalent Interactions ◽  
Covalent Interactions

<p>In the new millennium, the outbreak of new coronavirus has happened three times: SARS-CoV, MERS-CoV, and 2019-nCoV. Unfortunately, we still have no pharmaceutical weapons against the diseases caused by these viruses. The pandemic of 2019-nCoV reminds us of the urgency to search new drugs with totally different mechanism that may target the weaknesses specific to coronaviruses. Herein, we disclose a new targeted oxidation strategy (TOS II) leveraging non-covalent interactions potentially to oxidize and inhibit the activities of cytosolic thiol proteins via thiol/thiolate oxidation to disulfide (TOD). Quantum mechanical calculations show encouraging results supporting the feasibility to selectively oxidize thiol of targeted proteins via TOS II even in relatively reducing cytosolic microenvironments. Molecular docking against the two thiol proteases M<sup>pro</sup> and PL<sup>pro</sup> of 2019-nCoV provide evidence to support a TOS II mechanism for two experimentally identified anti-2019-nCoV disulfide oxidants: disulfiram and PX-12. Remarkably, disulfiram is an anti-alcoholism drug approved by FDA 70 years ago, thus it can be immediately used in phase III clinical trial for anti-2019-nCoV treatment. Finally, a preliminary list of promising TOS II drug candidates targeting the two thiol proteases of 2019-nCoV are proposed upon virtual screening of 32143 disulfides.</p>

scholarly journals Targeted Oxidation Strategy (TOS) for Potential Inhibition of Coronaviruses by Disulfiram — a 70-Year Old Anti-Alcoholism Drug

2020 ◽  
Author(s):  
Luyan Xu ◽  
Jiahui Tong ◽  
Yiran Wu ◽  
Suwen Zhao ◽  
Bo-Lin Lin
Keyword(s):  
Clinical Trial ◽  
New Drugs ◽  
Phase Iii ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
Phase Iii Clinical Trial ◽  
Drug Candidates ◽  
Thiol Proteases ◽  
Non Covalent Interactions ◽  
Covalent Interactions

<p>In the new millennium, the outbreak of new coronavirus has happened three times: SARS-CoV, MERS-CoV, and 2019-nCoV. Unfortunately, we still have no pharmaceutical weapons against the diseases caused by these viruses. The pandemic of 2019-nCoV reminds us of the urgency to search new drugs with totally different mechanism that may target the weaknesses specific to coronaviruses. Herein, we disclose a new targeted oxidation strategy (TOS II) leveraging non-covalent interactions potentially to oxidize and inhibit the activities of cytosolic thiol proteins via thiol/thiolate oxidation to disulfide (TOD). Quantum mechanical calculations show encouraging results supporting the feasibility to selectively oxidize thiol of targeted proteins via TOS II even in relatively reducing cytosolic microenvironments. Molecular docking against the two thiol proteases M<sup>pro</sup> and PL<sup>pro</sup> of 2019-nCoV provide evidence to support a TOS II mechanism for two experimentally identified anti-2019-nCoV disulfide oxidants: disulfiram and PX-12. Remarkably, disulfiram is an anti-alcoholism drug approved by FDA 70 years ago, thus it can be immediately used in phase III clinical trial for anti-2019-nCoV treatment. Finally, a preliminary list of promising TOS II drug candidates targeting the two thiol proteases of 2019-nCoV are proposed upon virtual screening of 32143 disulfides.</p>

scholarly journals The intermolecular interactions in the aminonitromethylbenzenes

2011 ◽  
Vol 9 (1) ◽  
pp. 94-105 ◽  
Author(s):  
Rafal Kruszynski ◽  
Tomasz Sieranski
Keyword(s):  
Hydrogen Bonds ◽  
Lone Pair ◽  
Quantum Mechanical ◽  
Stacking Interactions ◽  
Quantum Mechanical Calculations ◽  
Charge Redistribution ◽  
Intermolecular Hydrogen Bonds ◽  
Non Covalent Interactions ◽  
The One ◽  
Covalent Interactions

AbstractThe intermolecular non-covalent interactions in aminonitromethylbenzenes namely 2-methyl-4-nitroaniline, 4-methyl-3-nitroaniline, 2-methyl-6-nitroaniline, 4-amino-2,6-dinitrotoluene, 2-methyl-5-nitroaniline, 4-methyl-2-nitroaniline, 2,3-dimethyl-6-nitroaniline, 4,5-dimethyl-2-nitroaniline and 2-methyl-3,5-dinitroaniline were studied by quantum mechanical calculations at RHF/311++G(3df,2p) and B3LYP/311++G(3df,2p) level of theory. The calculations prove that solely geometrical study of hydrogen bonding can be very misleading because not all short distances (classified as hydrogen bonds on the basis of interaction geometry) are bonding in character. For studied compounds interaction energy ranges from 0.23 kcal mol−1 to 5.59 kcal mol−1. The creation of intermolecular hydrogen bonds leads to charge redistribution in donors and acceptors. The Natural Bonding Orbitals analysis shows that hydrogen bonds are created by transfer of electron density from the lone pair orbitals of the H-bond acceptor to the antibonding molecular orbitals of the H-bond donor and Rydberg orbitals of the hydrogen atom. The stacking interactions are the interactions of delocalized molecular π-orbitals of the one molecule with delocalized antibonding molecular π-orbitals and the antibonding molecular σ-orbital created between the carbon atoms of the second aromatic ring and vice versa.

scholarly journals Interactions between large molecules pose a puzzle for reference quantum mechanical methods

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yasmine S. Al-Hamdani ◽  
Péter R. Nagy ◽  
Andrea Zen ◽  
Dennis Barton ◽  
Mihály Kállay ◽  
...  
Keyword(s):  
Experimental Information ◽  
Quantum Mechanical ◽  
Interaction Energies ◽  
Small Organic Molecules ◽  
Large Molecules ◽  
Reference Information ◽  
Mechanical Methods ◽  
Non Covalent Interactions ◽  
Semi Empirical ◽  
Covalent Interactions

AbstractQuantum-mechanical methods are used for understanding molecular interactions throughout the natural sciences. Quantum diffusion Monte Carlo (DMC) and coupled cluster with single, double, and perturbative triple excitations [CCSD(T)] are state-of-the-art trusted wavefunction methods that have been shown to yield accurate interaction energies for small organic molecules. These methods provide valuable reference information for widely-used semi-empirical and machine learning potentials, especially where experimental information is scarce. However, agreement for systems beyond small molecules is a crucial remaining milestone for cementing the benchmark accuracy of these methods. We show that CCSD(T) and DMC interaction energies are not consistent for a set of polarizable supramolecules. Whilst there is agreement for some of the complexes, in a few key systems disagreements of up to 8 kcal mol−1 remain. These findings thus indicate that more caution is required when aiming at reproducible non-covalent interactions between extended molecules.

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