scholarly journals A comprehensive review on promising anti-viral therapeutic candidates identified against main protease from SARS-CoV-2 through various computational methods

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Ekampreet Singh ◽  
Rameez Jabeer Khan ◽  
Rajat Kumar Jha ◽  
Gizachew Muluneh Amera ◽  
Monika Jain ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Computational Methods ◽  
Structural Parameters ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Main Body ◽  
Interaction Patterns ◽  
Infected People ◽  
Chemical Structures ◽  
Exponential Trend

Abstract Background The COVID-19 pandemic caused by SARS-CoV-2 has shown an exponential trend of infected people across the planet. Crediting its virulent nature, it becomes imperative to identify potential therapeutic agents against the deadly virus. The 3-chymotrypsin-like protease (3CLpro) is a cysteine protease which causes the proteolysis of the replicase polyproteins to generate functional proteins, which is a crucial step for viral replication and infection. Computational methods have been applied in recent studies to identify promising inhibitors against 3CLpro to inhibit the viral activity. Main body of the abstract This review provides an overview of promising drug/lead candidates identified so far against 3CLpro through various in silico approaches such as structure-based virtual screening (SBVS), ligand-based virtual screening (LBVS) and drug-repurposing/drug-reprofiling/drug-retasking. Further, the drugs have been classified according to their chemical structures or biological activity into flavonoids, peptides, terpenes, quinolines, nucleoside and nucleotide analogues, protease inhibitors, phenalene and antibiotic derivatives. These are then individually discussed based on the various structural parameters namely estimated free energy of binding (ΔG), key interacting residues, types of intermolecular interactions and structural stability of 3CLpro-ligand complexes obtained from the results of molecular dynamics (MD) simulations. Conclusion The review provides comprehensive information of potential inhibitors identified through several computational methods thus far against 3CLpro from SARS-CoV-2 and provides a better understanding of their interaction patterns and dynamic states of free and ligand-bound 3CLpro structures.

scholarly journals Hierarchical Graph Representation of Pharmacophore Models

2020 ◽  
Vol 7 ◽  
Author(s):  
Garon Arthur ◽  
Wieder Oliver ◽  
Bareis Klaus ◽  
Seidel Thomas ◽  
Ibis Gökhan ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Large Scale ◽  
Md Simulations ◽  
Graph Representation ◽  
Feature Interaction ◽  
Full Potential ◽  
Interaction Patterns ◽  
Ligand Interaction ◽  
Hierarchical Graph ◽  
Pharmacophore Models

For the investigation of protein-ligand interaction patterns, the current accessibility of a wide variety of sampling methods allows quick access to large-scale data. The main example is the intensive use of molecular dynamics simulations applied to crystallographic structures which provide dynamic information on the binding interactions in protein-ligand complexes. Chemical feature interaction based pharmacophore models extracted from these simulations, were recently used with consensus scoring approaches to identify potentially active molecules. While this approach is rapid and can be fully automated for virtual screening, additional relevant information from such simulations is still opaque and so far the full potential has not been entirely exploited. To address these aspects, we developed the hierarchical graph representation of pharmacophore models (HGPM). This single graph representation enables an intuitive observation of numerous pharmacophore models from long MD trajectories and further emphasizes their relationship and feature hierarchy. The resulting interactive depiction provides an easy-to-apprehend tool for the selection of sets of pharmacophores as well as visual support for analysis of pharmacophore feature composition and virtual screening results. Furthermore, the representation can be adapted to include information involving interactions between the same protein and multiple different ligands. Herein, we describe the generation, visualization and use of HGPMs generated from MD simulations of two x-ray crystallographic derived structures of the human glucokinase protein in complex with allosteric activators. The results demonstrate that a large number of pharmacophores and their relationships can be visualized in an interactive, efficient manner, unique binding modes identified and a combination of models derived from long MD simulations can be strategically prioritized for VS campaigns.

scholarly journals Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of COVID-19 Main Protease: A Virtual Drug Repurposing Study

2020 ◽  
Author(s):  
Serdar Durdagi ◽  
Busecan Aksoydan ◽  
Berna Dogan ◽  
Kader Sahin ◽  
Aida Shahraki
Keyword(s):  
Virtual Screening ◽  
Clinical Investigation ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Binding Energies ◽  
New Drugs ◽  
Docking Simulations ◽  
New Drug ◽  
Main Protease ◽  
Glide Docking

<div>There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged preclinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs against</div><div>COVID-19 due to its pivotal role in the replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC) database in our drug repurposing study. Both apo and holo forms of target protein COVID-19 main proteases were used in virtual screening. Target proteins were retrieved from protein data bank (PDB IDs, 6M03 and 6LU7). Standard Precision (SP) protocol of Glide docking program of Maestro was used in docking. Compounds were then ranked based on their docking scores that represents binding energies. Top-30 compounds from each docking simulations were considered initially in short (10-ns) molecular dynamics (MD) simulations and their average binding energies using collected 1000 trajectories throughout the MD simulations were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Selected promising hit compounds based on average MM/GBSA scores were then used in long (100-ns) MD simulations. These numerical calculations showed that the following 6 compounds can be considered as COVID-19 Main Protease inhibitors: Lasinavir, Brecanavir, Telinavir, Rotigaptide, 1,3-Bis-(2-ethoxycarbonylchromon-5-yloxy)-2-(lysyloxy)propane and Pimelautide.</div>

scholarly journals Targeting Novel Coronavirus 2019: A Systematic Drug Repurposing Approach to Identify Promising Inhibitors Against 3C-like Proteinase and 2'-O-Ribose Methyltransferase

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Jha ◽  
Gizachew Muluneh Amera ◽  
Monika Jain ◽  
Ekampreet Singh ◽  
...  
Keyword(s):  
Drug Target ◽  
Structural Parameters ◽  
Physiological State ◽  
Drug Repurposing ◽  
Antiviral Drugs ◽  
Host Immune System ◽  
Infected People ◽  
Drug Molecules ◽  
Therapeutic Drugs ◽  
Novel Coronavirus

<div>The recent pandemic associated with 2019-nCoV, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify potential inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (ΔG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (ΔG= -9.8 kcal/mol) & Raltegravir (ΔG= -7.8 kcal/mol) for 3CLpro and Dolutegravir (ΔG= -9.4 kcal/mol) and Bictegravir (ΔG= -8.4 kcal/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against 2019-nCoV.</div>

scholarly journals Targeting Novel Coronavirus 2019: A Systematic Drug Repurposing Approach to Identify Promising Inhibitors Against 3C-like Proteinase and 2'-O-Ribose Methyltransferase

2020 ◽  
Author(s):  
Rameez Jabeer Khan ◽  
Rajat Jha ◽  
Gizachew Muluneh Amera ◽  
Monika Jain ◽  
Ekampreet Singh ◽  
...  
Keyword(s):  
Drug Target ◽  
Structural Parameters ◽  
Physiological State ◽  
Drug Repurposing ◽  
Antiviral Drugs ◽  
Host Immune System ◽  
Infected People ◽  
Drug Molecules ◽  
Therapeutic Drugs ◽  
Novel Coronavirus

<div>The recent pandemic associated with 2019-nCoV, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify potential inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (ΔG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (ΔG= -9.8 kcal/mol) & Raltegravir (ΔG= -7.8 kcal/mol) for 3CLpro and Dolutegravir (ΔG= -9.4 kcal/mol) and Bictegravir (ΔG= -8.4 kcal/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against 2019-nCoV.</div>

scholarly journals Discovery of a Bradykinin B2 Partial Agonist Profile of Raloxifene in a Drug Repurposing Campaign

2020 ◽  
Vol 22 (1) ◽  
pp. 257
Author(s):  
Patricia Gomez-Gutierrez ◽  
Juan J. Perez
Keyword(s):  
Virtual Screening ◽  
Molecular Mechanisms ◽  
Partial Agonist ◽  
Drug Repurposing ◽  
Cytokine Storm ◽  
Bradykinin Receptors ◽  
Screening Process ◽  
Bradykinin Antagonists ◽  
Illness Progression

Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine storm observed in patients with severe Covid-19. In the scope of a drug repurposing campaign undertaken to identify bradykinin antagonists, raloxifene was identified as prospective compound in a virtual screening process. The pharmacodynamics profile of raloxifene towards bradykinin receptors is reported in the present work, showing a weak selective partial agonist profile at the B2 receptor. In view of this new profile, its possible use as a therapeutical agent for the treatment of severe Covid-19 is discussed.

scholarly journals Haste makes waste: A critical review of docking‐based virtual screening in drug repurposing for SARS‐CoV‐2 main protease (M‐pro) inhibition

2021 ◽  
Author(s):  
Guillem Macip ◽  
Pol Garcia‐Segura ◽  
Júlia Mestres‐Truyol ◽  
Bryan Saldivar‐Espinoza ◽  
María José Ojeda‐Montes ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Critical Review ◽  
Drug Repurposing ◽  
Main Protease

scholarly journals Synthesis, Anti-Inflammatory Activity, and In Silico Study of Novel Diclofenac and Isatin Conjugates

2018 ◽  
Vol 2018 ◽  
pp. 1-11
Author(s):  
Musab Mohamed Ibrahim ◽  
Tilal Elsaman ◽  
Mosab Yahya Al-Nour
Keyword(s):  
Virtual Screening ◽  
Condensation Reaction ◽  
Docking Study ◽  
Positive Control ◽  
Inflammatory Activity ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
Chemical Structures ◽  
Anti Inflammatory

The design, synthesis, and development of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are respectable area of research. Novel Diclofenac Schiff’s bases (M1, M2, M4, M7, and M8) were designed and synthesized, and their respective chemical structures were deduced using various spectral tools (IR, 1H NMR, 13C NMR, and MS). The compounds were synthesized via Schiff’s condensation reaction and their anti-inflammatory activity was investigated applying the Carrageenan-induced paw edema model against Diclofenac as positive control. Percentage inhibition of edema indicated that all compounds were exhibiting a comparable anti-inflammatory activity as Diclofenac. Moreover, the anti-inflammatory activity was supported via virtual screening using molecular docking study. Interestingly compound M2 showed the highest in vivo activity (61.32% inhibition) when compared to standard Diclofenac (51.36% inhibition) as well as the best binding energy score (-10.765) and the virtual screening docking score (-12.142).

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