Movable type – potential of mean force method applied to the COVID-19 3c-like protease inhibition mechanism study, and drug repurposing screening

2020 ◽  
Author(s):  
Zheng Zheng ◽  
Kenneth Merz ◽  
Lance Westerhoff
Keyword(s):  
Drug Repurposing ◽  
Potential Of Mean Force ◽  
Inhibition Mechanism ◽  
Mechanism Study ◽  
Protease Inhibition ◽  
Force Method ◽  
Type Potential

scholarly journals Computational Evaluation of the COVID-19 3c-like Protease Inhibition Mechanism, and Drug Repurposing Screening

2020 ◽  
Author(s):  
Hao Liu ◽  
Tao Jiang ◽  
Wenlang Liu ◽  
Zheng Zheng
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Energy Method ◽  
Drug Repurposing ◽  
Inhibition Mechanism ◽  
Binding Affinities ◽  
Protease Inhibition ◽  
Drug Candidates ◽  
Experimental Drugs ◽  
Drugbank Database

<p>The rapid spread of the COVID-19 outbreak is now a global threat with over a million diagnosed cases and more than 70 thousand deaths. Specific treatments and effective drugs regarding such disease are in urgent need. To contribute to the drug discovery against COVID-19, we performed computational study to understand the inhibition mechanism of the COVID-19 3c-like protease, and search for possible drug candidates from approved or experimental drugs through drug repurposing screening against the DrugBank database. Two novel computational methods were applied in this study. We applied the “Consecutive Histogram Monte Carlo” (CHMC) sampling method for understanding the inhibition mechanism from studying the 2-D binding free energy landscape. We also applied the “Movable Type” (MT) free energy method for the lead compound screening by evaluating the binding free energies of the COVID-19 3c-like protease – inhibitor complexes. Lead compounds from the DrugBank database were first filtered using ligand similarity comparison to 19 published SARS 3c-like protease inhibitors. 70 selected compounds were then evaluated for protein-ligand binding affinities using the MT free energy method. 4 drug candidates with strong binding affinities and reasonable protein-ligand binding modes were selected from this study, <i>i.e.</i> Enalkiren (DB03395), Rupintrivir (DB05102), Saralasin (DB06763) and TRV-120027 (DB12199). </p>

scholarly journals Computational Evaluation of the COVID-19 3c-like Protease Inhibition Mechanism, and Drug Repurposing Screening

2020 ◽  
Author(s):  
Hao Liu ◽  
Tao Jiang ◽  
Wenlang Liu ◽  
Zheng Zheng
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Energy Method ◽  
Drug Repurposing ◽  
Inhibition Mechanism ◽  
Binding Affinities ◽  
Protease Inhibition ◽  
Drug Candidates ◽  
Experimental Drugs ◽  
Drugbank Database

<p>The rapid spread of the COVID-19 outbreak is now a global threat with over a million diagnosed cases and more than 70 thousand deaths. Specific treatments and effective drugs regarding such disease are in urgent need. To contribute to the drug discovery against COVID-19, we performed computational study to understand the inhibition mechanism of the COVID-19 3c-like protease, and search for possible drug candidates from approved or experimental drugs through drug repurposing screening against the DrugBank database. Two novel computational methods were applied in this study. We applied the “Consecutive Histogram Monte Carlo” (CHMC) sampling method for understanding the inhibition mechanism from studying the 2-D binding free energy landscape. We also applied the “Movable Type” (MT) free energy method for the lead compound screening by evaluating the binding free energies of the COVID-19 3c-like protease – inhibitor complexes. Lead compounds from the DrugBank database were first filtered using ligand similarity comparison to 19 published SARS 3c-like protease inhibitors. 70 selected compounds were then evaluated for protein-ligand binding affinities using the MT free energy method. 4 drug candidates with strong binding affinities and reasonable protein-ligand binding modes were selected from this study, <i>i.e.</i> Enalkiren (DB03395), Rupintrivir (DB05102), Saralasin (DB06763) and TRV-120027 (DB12199). </p>

scholarly journals Investigation of ammonium–lauric salt as shale swelling inhibitor and a mechanism study

2018 ◽  
Vol 37 (1-2) ◽  
pp. 49-60 ◽  
Author(s):  
Jie Zhang ◽  
Weimin Hu ◽  
Li Zhang ◽  
Tiehu Li ◽  
Dan Cai ◽  
...  
Keyword(s):  
Lauric Acid ◽  
Physical Adsorption ◽  
Drilling Fluid ◽  
Superior Performance ◽  
Inhibition Mechanism ◽  
Mechanism Study ◽  
X Ray Diffraction ◽  
Expansion Test ◽  
Mud Cake ◽  
Swelling Rate

In this work, a series of ammonium–lauric salts (ALS) was prepared with lauric acid and amines as small molecular shale swelling inhibitor. The inhibitors were screened by the linear expansion test first, and the result shows that the inhibitor prepared by lauric acid and diethylenetriamine with the mole ratio of 2:1 (ALS-2) displays excellent inhibition effect on the hydration expansion of bentonite. The inhibition of ALS-2 to bentonite was fully evaluated by various methods in the following work, including clay linear swelling test and particle distribution measurement. The results show that ALS-2 has superior performance to inhibit the hydration swelling and dispersion of bentonite, and the swelling rate of bentonite in 0.5% ALS-2 was reduced to 29.7%. In water-based drilling fluid, ALS-2 is compatible with the conventional additives, and it can improve the lubricity of the mud cake obviously after aged under 120°C. Besides, it can control the particle size of bentonite in water. The inhibition mechanism of the ammonium–lauric salts was discussed in detail through physical adsorption, scanning electron microscopy, X-ray diffraction, thermogravimetric analysis, and Fourier transform infrared spectroscopy.

scholarly journals Equilibrium Between Tri- and Tetra-Coordinate Chalcogenuranes Is Critical for Cysteine Protease Inhibition

2020 ◽  
Author(s):  
Gabriela Dias SIlva ◽  
Rodrigo L O R Cunha ◽  
Mauricio Domingues Coutinho Neto
Keyword(s):  
Cysteine Protease ◽  
Density Functional ◽  
Active Form ◽  
Sulfhydryl Group ◽  
Cysteine Proteases ◽  
Inhibition Mechanism ◽  
Direct Reaction ◽  
Exchange Reactions ◽  
Protease Inhibition ◽  
Biological Media

<div>There have been significant advances in the biological use of hypervalent selenium and tellurium compounds as cysteine protease inhibitors over the recent past. However, the full understanding of their reaction mechanisms in aqueous medium and the mechanism of cysteine proteases inhibition is still elusive. Kinetic studies suggest an irreversible inhibition mechanism, which was explained by forming a covalent bond between the enzyme sulfhydryl group and the chalcogen atom at its hypervalent state (+4). However, it is still unclear the active form of the inhibitor present in the aqueous biological media. To uncover this question, we performed a theoretical investigation using density functional theory (DFT). This study investigated chloride ligand exchange reactions by oxygen and sulfur nucleophiles on hypervalent selenium and tellurium compounds. All tetra- and tri-coordinate chalcogen compounds and distinct protonation states of the nucleophiles were considered, totaling 34 unique species, 7</div><div>nucleophiles and 155 free energies rections. We discovered that chloride is easily replaced by a nonprotonated nucleophile (SH<sup>–</sup> or OH<sup>– </sup>) in R<sub>2</sub>SeCl<sub>2</sub> . We also found that</div><div>tri-coordinate species are more stable than their tetra-coordinate counterparts, with selenoxide (R<sub>2</sub>SeO) protonation being strongly exergonic in acid pH. These results suggest that the protonated selenoxide (R<sub>2</sub>SeOH<sup>+</sup>) is the most probable active chemical species in biological media. The computed energetic profiles paint a possible picture for the selenurane activity, with successive exergonic steps leading to a covalent inhibition of thiol dependent enzymes, like cysteine proteases. A second less exergonic pathway has also been uncovered, with a direct reaction to chalcogenonium cation (R<sub>2</sub>SeCl<sup>+</sup>) as the inhibition step. The trends observed for the telluranes were similar, albeit with</div><div>more exergonic reactions and a stronger trend to form bonds with oxygen species then selenuranes.</div><div><br></div>

scholarly journals Multiscale Simulations of SARS-CoV-2 3CL Protease Inhibition with Aldehyde Derivatives. Role of Protein and Inhibitor Conformational Dynamics in the Reaction Mechanism

2020 ◽  
Author(s):  
Carlos A. Ramos-Guzmán ◽  
J. Javier Ruiz-Pernía ◽  
Iñaki Tuñón
Keyword(s):  
Proton Transfer ◽  
Noncovalent Complex ◽  
Conformational Dynamics ◽  
Aldehyde Group ◽  
Nucleophilic Attack ◽  
Inhibition Mechanism ◽  
Protease Inhibition ◽  
Activated State ◽  
3Cl Protease

<p>We here investigate the mechanism of SARS-CoV-2 3CL protease inhibition by one of the most promising families of inhibitors, those containing an aldehyde group as warhead. These compounds are covalent inhibitors that inactivate the protease forming a stable hemithioacetal complex. Inhibitor 11a is a potent inhibitor that has been already tested in vitro and in animals. Using a combination of classical and QM/MM simulations we determined the binding mode of the inhibitor into the active site and the preferred rotameric state of the catalytic histidine. In the noncovalent complex the aldehyde group is accommodated into the oxyanion hole formed by the NH main chain groups of residues 143 to 145. In this pose, P1-P3 groups of the inhibitor mimic the interactions established by the natural peptide substrate. The reaction is initiated with the formation of the catalytic dyad ion pair after a proton transfer from Cys145 to His41. From this activated state, covalent inhibition proceeds with the nucleophilic attack of the deprotonated Sg atom of Cys145 to the aldehyde carbon atom and a water mediated proton transfer from the Ne atom of His41 to the aldehyde oxygen atom. Our proposed reaction transition state structure is validated by comparison with x-ray data of recently reported inhibitors, while the activation free energy obtained from our simulations agrees with the experimentally derived value, supporting the validity of our findings. Our study stresses the interplay between the conformational dynamics of the inhibitor and the protein with the inhibition mechanism and the importance of including conformational diversity for accurate predictions about the inhibition of the main protease of SARS-CoV-2. The conclusions derived from our work can also be used to rationalize the behavior of other recently proposed inhibitor compounds, including aldehydes and ketones with high inhibitory potency.</p>

scholarly journals Serpin Inhibition Mechanism: A Delicate Balance between Native Metastable State and Polymerization

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Mohammad Sazzad Khan ◽  
Poonam Singh ◽  
Asim Azhar ◽  
Asma Naseem ◽  
Qudsia Rashid ◽  
...  
Keyword(s):  
Metastable State ◽  
Critical Role ◽  
Stable State ◽  
Inhibition Mechanism ◽  
Inhibitory Mechanism ◽  
Protease Inhibition ◽  
Native Form ◽  
Mechanism Of Inhibition ◽  
Reactive Center ◽  
Functionally Diverse

The serpins (serine proteinase inhibitors) are structurally similar but functionally diverse proteins that fold into a conserved structure and employ a unique suicide substrate-like inhibitory mechanism. Serpins play absolutely critical role in the control of proteases involved in the inflammatory, complement, coagulation and fibrinolytic pathways and are associated with many conformational diseases. Serpin's native state is a metastable state which transforms to a more stable state during its inhibitory mechanism. Serpin in the native form is in the stressed (S) conformation that undergoes a transition to a relaxed (R) conformation for the protease inhibition. During this transition the region called as reactive center loop which interacts with target proteases, inserts itself into the center of β-sheet A to form an extra strand. Serpin is delicately balanced to perform its function with many critical residues involved in maintaining metastability. However due to its typical mechanism of inhibition, naturally occurring serpin variants produces conformational instability that allows insertion of RCL of one molecule into the β-sheet A of another to form a loop-sheet linkage leading to its polymerization and aggregation. Thus understanding the molecular basis and amino acid involved in serpin polymerization mechanism is critical to devising strategies for its cure.

scholarly journals Experimental study and computational modelling of cruzain cysteine protease inhibition by dipeptidyl nitriles

2018 ◽  
Vol 20 (37) ◽  
pp. 24317-24328 ◽  
Author(s):  
Alberto Monteiro Dos Santos ◽  
Lorenzo Cianni ◽  
Daniela De Vita ◽  
Fabiana Rosini ◽  
Andrei Leitão ◽  
...  
Keyword(s):  
Experimental Study ◽  
Cysteine Protease ◽  
Computational Modelling ◽  
Inhibition Mechanism ◽  
Protease Inhibition ◽  
Reaction Inhibition

A combined computational and experimental study aimed to gain insights into the reaction inhibition mechanism of cruzain by dipeptidyl nitriles.

scholarly journals Equilibrium Between Tri- and Tetra-Coordinate Chalcogenuranes Is Critical for Cysteine Protease Inhibition

2020 ◽  
Author(s):  
Gabriela Dias SIlva ◽  
Rodrigo L O R Cunha ◽  
Mauricio Domingues Coutinho Neto
Keyword(s):  
Cysteine Protease ◽  
Density Functional ◽  
Active Form ◽  
Sulfhydryl Group ◽  
Cysteine Proteases ◽  
Inhibition Mechanism ◽  
Direct Reaction ◽  
Exchange Reactions ◽  
Protease Inhibition ◽  
Biological Media

<div>There have been significant advances in the biological use of hypervalent selenium and tellurium compounds as cysteine protease inhibitors over the recent past. However, the full understanding of their reaction mechanisms in aqueous medium and the mechanism of cysteine proteases inhibition is still elusive. Kinetic studies suggest an irreversible inhibition mechanism, which was explained by forming a covalent bond between the enzyme sulfhydryl group and the chalcogen atom at its hypervalent state (+4). However, it is still unclear the active form of the inhibitor present in the aqueous biological media. To uncover this question, we performed a theoretical investigation using density functional theory (DFT). This study investigated chloride ligand exchange reactions by oxygen and sulfur nucleophiles on hypervalent selenium and tellurium compounds. All tetra- and tri-coordinate chalcogen compounds and distinct protonation states of the nucleophiles were considered, totaling 34 unique species, 7</div><div>nucleophiles and 155 free energies rections. We discovered that chloride is easily replaced by a nonprotonated nucleophile (SH<sup>–</sup> or OH<sup>– </sup>) in R<sub>2</sub>SeCl<sub>2</sub> . We also found that</div><div>tri-coordinate species are more stable than their tetra-coordinate counterparts, with selenoxide (R<sub>2</sub>SeO) protonation being strongly exergonic in acid pH. These results suggest that the protonated selenoxide (R<sub>2</sub>SeOH<sup>+</sup>) is the most probable active chemical species in biological media. The computed energetic profiles paint a possible picture for the selenurane activity, with successive exergonic steps leading to a covalent inhibition of thiol dependent enzymes, like cysteine proteases. A second less exergonic pathway has also been uncovered, with a direct reaction to chalcogenonium cation (R<sub>2</sub>SeCl<sup>+</sup>) as the inhibition step. The trends observed for the telluranes were similar, albeit with</div><div>more exergonic reactions and a stronger trend to form bonds with oxygen species then selenuranes.</div><div><br></div>

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