scholarly journals Computational Discovery of Small Drug-like Compounds as Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Alexander M. Andrianov ◽  
Yuri V. Kornoushenko ◽  
Anna D. Karpenko ◽  
Ivan P. Bosko ◽  
Alexander Tuzikov
Keyword(s):  
Active Site ◽  
Binding Free Energy ◽  
Antiviral Agents ◽  
Binding Pocket ◽  
Van Der Waals Interactions ◽  
Salt Bridges ◽  
Enzyme Active Site ◽  
High Affinity ◽  
Affinity Ligand ◽  
Main Protease

A computational approach to in silico drug discovery was carried out to identify small druglike compounds able to show structural and functional mimicry of the high affinity ligand X77, potent non-covalent inhibitor of SARS-COV-2 main protease (MPro). In doing so, the X77-mimetic candidates were predicted based on the crystal X77-MPro structure by a public web-oriented virtual screening platform Pharmit. Models of these candidates bound to SARS-COV-2 MPro were generated by molecular docking and optimized by the quantum chemical method PM7. At the final point, analysis of the interaction modes of the identified compounds with MPro 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 MPro. Insights into the ligandMPro models indicate that all identified compounds may effectively block the binding pocket of SARS-CoV-2 MPro, in line with the low values of binding free energy and dissociation constant. Mechanism of binding of these compounds to MPro is generally provided by hydrogen bonds and van der Waals interactions with the functionally important residues of the enzyme active site, such as His-41, Leu-141, His-163, Met-165, and Glu166. In addition, individual ligands form salt bridges with the MPro residues His-163 or Glu-166 and participate in specific - interactions with the catalytic dyad residue His-41. 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 MPro.<br>

scholarly journals Computational Discovery of Small Drug-like Compounds as Potential Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Alexander M. Andrianov ◽  
Yuri V. Kornoushenko ◽  
Anna D. Karpenko ◽  
Ivan P. Bosko ◽  
Alexander Tuzikov
Keyword(s):  
Active Site ◽  
Binding Free Energy ◽  
Antiviral Agents ◽  
Binding Pocket ◽  
Van Der Waals Interactions ◽  
Salt Bridges ◽  
Enzyme Active Site ◽  
High Affinity ◽  
Affinity Ligand ◽  
Main Protease

A computational approach to in silico drug discovery was carried out to identify small druglike compounds able to show structural and functional mimicry of the high affinity ligand X77, potent non-covalent inhibitor of SARS-COV-2 main protease (MPro). In doing so, the X77-mimetic candidates were predicted based on the crystal X77-MPro structure by a public web-oriented virtual screening platform Pharmit. Models of these candidates bound to SARS-COV-2 MPro were generated by molecular docking and optimized by the quantum chemical method PM7. At the final point, analysis of the interaction modes of the identified compounds with MPro 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 MPro. Insights into the ligandMPro models indicate that all identified compounds may effectively block the binding pocket of SARS-CoV-2 MPro, in line with the low values of binding free energy and dissociation constant. Mechanism of binding of these compounds to MPro is generally provided by hydrogen bonds and van der Waals interactions with the functionally important residues of the enzyme active site, such as His-41, Leu-141, His-163, Met-165, and Glu166. In addition, individual ligands form salt bridges with the MPro residues His-163 or Glu-166 and participate in specific - interactions with the catalytic dyad residue His-41. 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 MPro.<br>

scholarly journals Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 1004
Author(s):  
Mahmoud A. El Hassab ◽  
Mohamed Fares ◽  
Mohammed K. Abdel-Hamid Amin ◽  
Sara T. Al-Rashood ◽  
Amal Alharbi ◽  
...  
Keyword(s):  
Drug Design ◽  
Active Site ◽  
Binding Free Energy ◽  
Stable Complex ◽  
Active Site Residues ◽  
Structure Based Drug Design ◽  
Enzyme Active Site ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Covalent Docking

Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.

scholarly journals Identification of Cucumis Sativus Urease as a Potential Urea Binding Enzyme by Computational Methods

2020 ◽  
Vol 11 (2) ◽  
pp. 9184-9200
Keyword(s):  
Binding Affinity ◽  
Cucumis Sativus ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Binding Pocket ◽  
Pigeon Pea ◽  
Energy Calculation ◽  
High Nitrogen Content ◽  
High Affinity ◽  
Nitrogenous Fertilizer

Urea is the most commonly used solid nitrogenous fertilizer owing to the fact that it contains high nitrogen content and also plays a significant role in the growth of plants. Many plant ureases catalyze the conversion of urea to ammonia and carbon dioxide. Identification of high-affinity plant ureases is considered to be one of the burning topics among several researchers for the development of Genetically Modified (GMO) crops. In the current study, the binding affinity of urea was compared with some of the plant ureases. In regard to this Pigeon pea Urease (PpU) was fixed as a reference to predict the binding pocket and thereby compare the binding affinity with urea. Cucumis sativus Urease (CsU) and Fragaria vesca Urease (FvU) were screened for comparison. Performing Molecular Dynamics (MD) simulation, molecular docking, and binding free energy calculation, it was observed that the structure of CsU was relatively stable and had a greater affinity of -3.37 kcal/mol with urea when compared with PpU and FvU. Predominantly, we report here that comparatively, CsU is a potential urea binding enzyme. Our findings in this study would be a useful tool in engineering novel high-affinity plant ureases drugs.

scholarly journals IN Silico Approach of Some Selected Honey Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors

2020 ◽  
Author(s):  
Heba Hashem
Keyword(s):  
Active Site ◽  
Life Cycles ◽  
High Binding Energy ◽  
Protease Inhibition ◽  
Enzyme Active Site ◽  
Therapeutic Drugs ◽  
Main Protease ◽  
The World ◽  
Essential Enzyme ◽  
The Way

<p>The huge attack of coronavirus disease 2019 (COVID-19) over all the world forces the researcher around the world to study the crystal structure of the main protease M<sup>pro</sup> ( 3-chymotrypsin-like cysteine enzyme) which is the essential enzyme for coronavirus processing the polyproteins and its life cycles. And by the way, the inhibition of this enzyme active site becomes the target of all scientists of drug discovery in order to overcome this disease. In this study, we have used the molecular modeling approach to evaluate the activity of different active compounds from honeybee and propolis to inhibit the presented sars-cov-2 main protease via Schrödinger Maestro v10.1. the presented study resulted in six main compounds possess high binding energy with the receptor active site of COVID-19 main protease. we hope this study being the way for honeybee constitution as an effective ligand for sars-cov-2 main protease inhibition and be in the medicinal study of anti-COVID-19 therapeutic drugs.</p>

scholarly journals Investigation of Carboxylic Acid Isosteres for Inhibition of the Human SIRT5 Lysine Deacylase Enzyme

2021 ◽  
Author(s):  
Nima Rajabi ◽  
Alexander L. Nielsen ◽  
Tobias N. Hansen ◽  
Huy T. Nguyen ◽  
Michael Bæk ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Posttranslational Modifications ◽  
Active Site ◽  
Drug Target ◽  
Mitochondrial Enzymes ◽  
Enzyme Active Site ◽  
High Affinity ◽  
Future Drug ◽  
Cell Inhibition ◽  
Sar Study

Sirtuin 5 (SIRT5) is a protein lysine deacylase enzyme that regulates diverse biology by hydrolyzing -N-carboxyacyllysine posttranslational modifications in the cell. Inhibition of SIRT5 has been linked to potential treatment of several cancers but potent compounds with activity in cells have been lacking. Here we developed mechanism-based inhibitors that incorporate isosteres of a carboxylic acid residue that is important for high-affinity binding to the enzyme active site. By masking of the tetrazole moiety of the most potent candidate from our initial SAR study, we achieved potent and cytoselective growth inhibition for the treatment of SIRT5-dependent leukemic cancer cell lines in culture. Thus, we provide an efficient, cellularly active small molecule that targets SIRT5, which can help elucidate its function and potential as a future drug target. This work shows that masked biosisosteres of carboxylic acids are viable chemical motifs for the development of inhibitors that target mitochondrial enzymes, which may have applications beyond the sirtuin field.

scholarly journals A Computational Approach to Explore the Interaction of Semisynthetic Nitrogenous Heterocyclic Compounds with the SARS-CoV-2 Main Protease

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 18
Author(s):  
Alejandro Llanes ◽  
Héctor Cruz ◽  
Viet D. Nguyen ◽  
Oleg V. Larionov ◽  
Patricia L. Fernández
Keyword(s):  
Active Site ◽  
Heterocyclic Compounds ◽  
Natural Compound ◽  
Antiviral Agents ◽  
Docking Simulation ◽  
Energy Estimates ◽  
Main Protease ◽  
Realistic Representation ◽  
L1 And L2 ◽  
Synthetic Derivatives

In the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic, numerous attempts have been made to discover new potential antiviral molecules against its causative agent, SARS-CoV-2, many of which focus on its main protease (Mpro). We hereby used two approaches based on molecular docking simulation to explore the interaction of four libraries of semisynthetic nitrogenous heterocyclic compounds with Mpro. Libraries L1 and L2 contain 52 synthetic derivatives of the natural compound 2-propylquinoline, whereas libraries L3 and L4 contain 65 compounds synthesized using the natural compound physostigmine as a precursor. Validation through redocking suggested that the rigid receptor and flexible receptor approaches used for docking were suitable to model the interaction of this type of compounds with the target protein, although the flexible approach seemed to provide a more realistic representation of interactions within the active site. Using empirical energy score thresholds, we selected 58 compounds from the four libraries with the most favorable energy estimates. Globally, favorable estimates were obtained for molecules with two or more substituents, putatively accommodating in three or more subsites within the Mpro active site. Our results pave the way for further experimental evaluation of the selected compounds as potential antiviral agents against SARS-CoV-2.

scholarly journals Deciphering the Binding Mechanism of Dexamethasone Against SARS-CoV-2 Main Protease: Computational Molecular Modelling Approach

2020 ◽  
Author(s):  
Shafi Ullah Khan ◽  
Thet.thet Htar
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonds ◽  
Active Site ◽  
Binding Mechanism ◽  
Protein Targets ◽  
High Affinity ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Covalent Inhibitor ◽  
Modelling Approach

<p>At present, there are no proven agents for the treatment of 2019 coronavirus disease (COVID-19). The available evidence has not allowed guidelines to clearly recommend any drugs outside the context of clinical trials. One of the most important SARS-CoV-2 protein targets for therapeutics is the 3C-like protease (main protease, Mpro). Here in this study we utilize the recently published 6W63 crystal structure of Mpro complexed with a non-covalent inhibitor X77. Various docking methods FRED, HYBRID, CDOCKER and LEADFINDER tools were benchmark to optimally re-dock the co-crystal ligand within the active site of SARS-COV-2 Mpro. This study was restricted to molecular docking without validation by molecular dynamics simulations. CDOCKER was found to depict the exact binding of co-crystal ligand having lowest RMSD of less than 2 A. Interactions with the SARS-COV-2 Mpro may play a key role in fighting against viruses. Dexamethasone was found to bind with a high affinity to the same sites of the SARS-COV-2 Mpro than the Remdesivir. Dexamethasone was forming six hydrogen bonds compared to the three hydrogen bonds formed by Remdesivir within the active site of SARS-COV-2 Mpro. LEU141, GLY143, HIS163, GLU166, GLN192 were the key amino acid residue of SAR-COV-2 Mpro involved in stabilizing the complex between Dexamethasone and SARS-COV-2 Mpro. The results suggest the effectiveness of Dexamethasone as potent drugs against SARS-CoV-2 since it bind tightly to its Mpro. In addition, the results also suggest that dexamethasone as top antiviral treatments option than the Remdesivir with high potential to fight the SARS-CoV-2.</p>

Screening for Potential Traditional Herbal Inhibitors Against 3-Chymotrypsin-Like Main Protease (3CLpro) from Four Different Coronaviruses-: An in-silico Approach

Coronaviruses ◽  
2021 ◽  
Vol 02 ◽  
Author(s):  
Prachi Singh ◽  
Ardra P ◽  
Hariprasad V.R. ◽  
Babu U.V. ◽  
Mohamed Rafiq ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Broad Spectrum ◽  
Active Site ◽  
Dissociation Constants ◽  
Substrate Binding ◽  
Binding Pocket ◽  
Health Concern ◽  
Ocimum Sanctum ◽  
Prunella Vulgaris ◽  
Main Protease

Background: The recent outbreak of the COVID-19 pandemic has raised a global health concern due to the unavailability of any vaccines or drugs. The repurposing of traditional herbs with broad-spectrum anti-viral activity can be explored to control or prevent a pandemic. Objective: The 3-chymotrypsin-like main protease (3CLpro), also referred to as the “Achilles’ heel” of the coronaviruses (CoVs), is highly conserved among CoVs and is a potential drug target. 3CLpro is essential for the virus’s life cycle. The objective of the study was to screen and identify broad-spectrum natural phytoconstituents against the conserved active site and substrate-binding site of 3CLpro of HCoVs. Methods: Herein, we applied the computational strategy based on molecular docking to identify potential phytoconstituents for the non-covalent inhibition of the main protease 3CLpro from four different CoVs, namely, SARS-CoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Results: Our study shows that natural phytoconstituents in Triphala (a blend of Emblica Officinalis fruit, Terminalia bellerica fruit, and Terminalia chebula fruit), namely chebulagic acid, chebulinic acid, and elagic acid, exhibited the highest binding affinity and lowest dissociation constants (Ki), against the conserved 3CLpro main protease of SARSCoV-2, SARS-CoV, HCoV-HKU1, and HCoV-229E. Besides, phytoconstituents of other herbs like Withania somnifera, Glycyrrhiza glabra, Hyssopus officinalis, Camellia sinensis, Prunella vulgaris, and Ocimum sanctum also showed good binding affinity and lower Ki against the active site of 3CLpro. The top-ranking phytoconstituents’ binding interactions clearly showed a strong and stable interactions with amino acid residues in the catalytic dyad (CYS-HIS) and substrate-binding pocket of the 3CLpro main proteases. Conclusion: This study provides a valuable scaffold for repurposing traditional herbs with anti-CoV activity to combat SARS-CoV-2 and other HCoVs until the discovery of new therapies.

scholarly journals Repurposing of FDA-approved Drugs against Active Site and Potential Allosteric Drug Binding Sites of COVID-19 Main Protease

2021 ◽  
Author(s):  
Merve Yuce ◽  
Erdem Cicek ◽  
Tuğçe İnan ◽  
Aslıhan Başak Dağ ◽  
Özge Kürkçüoğlu ◽  
...  
Keyword(s):  
Active Site ◽  
Social Life ◽  
Binding Free Energy ◽  
Antiviral Drug ◽  
Drug Binding ◽  
Allosteric Site ◽  
Main Protease ◽  
Allosteric Sites ◽  
Approved Drugs ◽  
Fda Approved Drugs

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, FDA-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. 14 best molecule hits for the active site of Mpro are determined. 6 of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and -42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infection

scholarly journals Non-Active Site Mutants of HIV-1 Protease Influence Resistance and Sensitization Towards Protease Inhibitors

2020 ◽  
Author(s):  
Tomas Bastys ◽  
Vytautas Gapsys ◽  
Hauke Walter ◽  
Eva Heger ◽  
Nadezhda T Doncheva ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Active Site ◽  
Binding Free Energy ◽  
Binding Pocket ◽  
Antiretroviral Drugs ◽  
Inhibitor Binding ◽  
Ic50 Values ◽  
Hiv 1

Abstract BackgroundHIV-1 can develop resistance to antiretroviral drugs, mainly through mutations within the target regions of the drugs. In HIV-1 protease, a majority of resistance-associated mutations that develop in response to the therapy with protease inhibitors are found in the protease’s active site that serves also as a binding pocket for the protease inhibitors, thus directly impacting the protease-inhibitor interactions. Some resistance-associated mutations, however, are found in more distant regions, and the exact mechanisms how these mutations affect protease-inhibitor interactions are unclear. Furthermore, some of these mutations, e.g. N88S and L76V, do not only induce resistance to the currently administered drugs, but contrarily induce sensitivity towards other drugs. In this study, mutations N88S and L76V, along with two other resistance-associated mutations, M46I and I84V, are analysed by means of molecular dynamics simulations to investigate their role in complexes of the protease with different inhibitors and in different background sequence contexts.ResultsUsing these simulations for alchemical calculations to estimate the effects of mutations M46I, I84V, N88S, and L76V on binding free energies shows they are in general in line with the mutations’ effect on IC50 values. For the primary mutation L76V, however, the presence of a background mutation M46I in our analysis influences whether the unfavourable effect of L76V on inhibitor binding is sufficient to outweigh the accompanying reduction in catalytic activity of the protease. Finally, we show that L76V and N88S changes the hydrogen bond stability of these residues with residues D30/K45 and D30/T31/T74, respectively.ConclusionsWe demonstrate that estimating the effect of both binding pocket and distant mutations on inhibitor binding free energy using alchemical calculations can reproduce their effect on the experimentally measured IC50 values. We show that distant site mutations L76V and N88S affect the hydrogen bond network in the protease’s active site, which offers an explanation for the indirect effect of these mutations on inhibitor binding. This work thus provides valuable insights on interplay between primary and background mutations and mechanisms how they affect inhibitor binding.

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