scholarly journals Perspectives of a myosin motor activator agent with increased selectivity

2018 ◽  
Vol 96 (7) ◽  
pp. 676-680
Author(s):  
Péter Nánási ◽  
István Komáromi ◽  
János Almássy
Keyword(s):  
In Silico ◽  
Clinical Performance ◽  
Ryanodine Receptors ◽  
In Silico Analysis ◽  
Docking Studies ◽  
Cardiac Myosin ◽  
In Silico Docking ◽  
Myosin Motor ◽  
Omecamtiv Mecarbil ◽  
Silico Analysis

Clinical treatment of heart failure is still not fully solved. A novel class of agents, the myosin motor activators, acts directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. Omecamtiv mecarbil, the lead molecule of this group, is now in human phase 3 displaying promising clinical performance. However, omecamtiv mecarbil is not selective to myosin, because it readily binds to and activates cardiac ryanodine receptors (RyR-2), an effect that may cause complications in case of overdose. In this study, in silico analysis was performed to investigate the docking of omecamtiv mecarbil and other structural analogues to cardiac myosin heavy chain and RyR-2 to select the structure that has a higher selectivity to myosin over RyR-2. In silico docking studies revealed that omecamtiv mecarbil has comparable affinity to myosin and RyR-2: the respective Kd values are 0.60 and 0.87 μmol/L. Another compound, CK-1032100, has much lower affinity to RyR-2 than omecamtiv mecarbil, while it still has a moderate affinity to myosin. It was concluded that further research starting from the chemical structure of CK-1032100 may result a better myosin activator burdened probably less by the RyR-2 binding side effect. It also is possible, however, that the selectivity of omecamtiv mecarbil to myosin over RyR-2 cannot be substantially improved, because similar moieties seem to be responsible for the high affinity to both myosin and RyR-2.

scholarly journals Identification, Characterization, and In Silico Analysis of New Imine Reductases From Native Streptomyces Genomes

2021 ◽  
Vol 1 ◽  
Author(s):  
César Iglesias ◽  
Ariel Tijman ◽  
Gonzalo López ◽  
María Inés Lapaz ◽  
María Julia Pianzzola ◽  
...  
Keyword(s):  
In Silico ◽  
Reductase Activity ◽  
In Silico Analysis ◽  
Bioinformatic Analysis ◽  
Docking Studies ◽  
Secondary Amines ◽  
Sequence Motif ◽  
Optically Pure ◽  
Prochiral Ketone ◽  
Silico Analysis

The development of biocatalytic tools for the synthesis of optically pure amines has been the focus of abundant research in recent years. Among other enzymes, imine reductases have attracted much attention associated with the possibility of attaining chiral secondary amines. Furthermore, the reductive aminase activity associated with some of these enzymes has facilitated the production of optically pure amines from a prochiral ketone, a transformation that opens doors to an incredible array of products. In this work, the genomes from native Streptomyces strains isolated in our lab have been explored on the search for novel imine reductases. Application of different structural criteria and sequence motif filters allowed the identification of two novel enzymes, Ss-IRED_S and Ss-IRED_R. While the former presented outstanding activity towards bulky cyclic imine substrates, the latter presented reductive aminase activity with the assayed ketones. A bioinformatic analysis based on modeling and docking studies was performed in order to explain the differences in enzyme activity, searching for additional criteria that could be used to analyze enzyme candidates in silico, providing additional tools for enzyme selection for a particular application. Our findings suggest that imine reductase activity could be predicted by this analysis, overall accounting for the number of docking positions that meet the catalytic requirements.

scholarly journals Design, Molecular Docking And In Silico Analysis Of Analogues Of Chloroquine And Hydroxychloroquine Against SARs-COV-2 Target (6w63.pdb)

2020 ◽  
Author(s):  
Naruka Solomon Yakubu ◽  
Olanike Catherine Poyi ◽  
Ezikiel Olabisi Afolabi
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Target Prediction ◽  
In Silico Analysis ◽  
Docking Studies ◽  
Biologically Active ◽  
Dynamic Simulations ◽  
Comparable Activity ◽  
Silico Analysis

Abstract Computer-aided drug design has been an effective strategy and approach to discover, develop, analyze, accelerate and economize design and development of drugs and biologically active molecules. A total of twelve analogues of chloroquine (CQ) and hydroxychloroquine (HCQ) were designed and virtually analyzed using PyRx software, Molinspiration, Swiss ADME, Swiss-Target Prediction software and ProTox-II-Prediction of toxicity platform. Based on the docking studies carried out using Autodock vina, five analogues; H-368 (-6.0 Kcal/mol), H-372 (--6.0 Kcal/mol), H-156 (-5.9 Kcal/mol), H-139 (-5.7 Kcal/mol), C-136 (-5.7 Kcal/mol) exhibited higher binding affinity compared to HCQ(-5.5 Kcal/mol), while all twelve analogues exhibited higher binding affinity compared to CQ (-4.5Kcal/mol). In silico analysis of toxicity profile of this analogues shows a lower potential to toxicity and a comparable activity on some major isoforms of cytochrome P450. But unlike the parent molecules, both H-139 and H-156 are substrates of P-glycoproteins (P-gp) which implies that these analogues possess high clearance and less pharmacokinetic-related drug-drug interactions compared to the parent molecules. Herein we propose these analogues as potential inhibitors or lead compounds against the coronavirus with a view of conducting more molecular dynamic simulations, synthesizing and conducting in vitro studies on them.

scholarly journals Omecamtiv Mecarbil: A Myosin Motor Activator Agent with Promising Clinical Performance and New in vitro Results

2018 ◽  
Vol 25 (15) ◽  
pp. 1720-1728 ◽  
Author(s):  
Peter Nanasi ◽  
Istvan Komaromi ◽  
Marta Gaburjakova ◽  
Janos Almassy
Keyword(s):  
Side Effects ◽  
Clinical Data ◽  
Clinical Performance ◽  
Ryanodine Receptors ◽  
Inotropic Effect ◽  
Myosin Motor ◽  
Rate Dependent ◽  
Proarrhythmic Risk ◽  
Omecamtiv Mecarbil

Background: Clinical treatment of heart failure is still suffering from limited efficacy and unfavorable side effects. The recently developed group of agents, the myosin motor activators, act directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. The lead molecule, omecamtiv mecarbil is now in human 3 stage. In addition to the promising clinical data published so far, there are new in vitro results indicating that the effect of omecamtiv mecarbil on contractility is rate-dependent. Furthermore, omecamtiv mecarbil was shown to activate cardiac ryanodine receptors, an effect that may carry proarrhythmic risk. Methods: These new results, together with the controversial effects of the drug on cardiac oxygen consumption, are critically discussed in this review in light of the current literature on omecamtiv mecarbil. Results: In therapeutically relevant concentrations the beneficial inotropic effect of the agent is not likely affected by these new results - in accordance with the good clinical data. At supratherapeutic concentrations, however, activation of cardiac ryanodine receptors may increase arrhythmia propensity, and the stronger effect on diastolic than systolic cell shortening, observed at higher pacing frequencies, may decrease or offset the inotropic effect of omecamtiv mecarbil. Conclusion: Further studies with definitely supratherapeutical concentrations of omecamtiv mecarbil should be designed to map the actual risk of these potentially harmful side-effects.

scholarly journals In Silico Analysis of Forskolin as a Potential Inhibitor of SARS-CoV-2

2021 ◽  
Author(s):  
Arti Kumari ◽  
Prashant Kumar ◽  
Manindra Kumar ◽  
Jainendra Kumar
Keyword(s):  
In Silico ◽  
Antiviral Agent ◽  
In Silico Analysis ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Health Crisis ◽  
In Silico Docking ◽  
Protein Protein Interaction ◽  
Global Pandemic ◽  
Silico Analysis

Coronavirus disease 2019 (COVID–19) has spread rapidly as global pandemic affecting 187 countries/ regions and emerged as worldwide health crisis. Potential antiviral drugs used for the SARS -CoV-2 in clinical treatments have side effects. However, emergency vaccines are in use but despite that increase in the coronavirus cases are alarming. Thus, it is utmost need of safer antiviral agent to treat or inhibit the viral infection. Forskolin has been reported as a possible antiviral-agent. This molecule was docked with ACE2 receptor of human which is the target for the binding of S1 unit of viral S protein of SARS-CoV- 2. In silico docking was carried out on SwissDock, PatchDock and FireDock servers. The docked ACE2 structure was further docked with the RBD of the spike protein. Forskolin is able to H-bond with the hACE2 and ACE2-forskolin fails to interact with the receptor-binding domain (RBD) of the Spike protein of SARS-CoV-2. Instead, viral RBD is repulsed by the diterpene molecule through obliteration and reciprocated binding. We report first that forskolin plays a crucial role in the inhibition of protein-protein interaction of RBD and ACE2 when docked with either of the protein.

scholarly journals In Silico Analysis on Docking Studies of Haemolysin Protein in Vibrio Paraheamolyticus

2017 ◽  
Vol 10 (4) ◽  
pp. 1879-1886 ◽  
Author(s):  
Arunkumar T. ◽  
Archana Vasuki K. ◽  
Narendrakumar G.
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Docking Studies ◽  
Silico Analysis

scholarly journals Are the SARS-CoV-2 Variants Greater Threats? - An In Silico Analysis of the Spike Protein

2021 ◽  
Vol 8 (2) ◽  
Author(s):  
Wilson J ◽  
◽  
Sokolova V ◽  
Ji H F ◽  
◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Docking Studies ◽  
Binding Affinities ◽  
S Protein ◽  
Preventative Measures ◽  
Global Pandemic ◽  
Production And Distribution ◽  
In Silico Molecular Docking ◽  
Silico Analysis

March 2020 marked the beginning of a global pandemic caused by SARSCoV- 2. With the development, production and distribution of several vaccines there are hopes to an end in sight. However, with the emergence of several mutated viral strains concerns are mounting as to the effectiveness of the current treatments and preventative measures against the new strains. Herein we analyzed and compared the interaction of the SARS-CoV-2 Spike (S) protein and its variants with human Angiotensin Converting Enzyme (ACE-2) and the binding affinities of several possible S-protein inhibitors with these variants via in silico molecular docking studies. The binding affinities of all the variants to ACE- 2 are less than that of SARS-CoV-2, indicating they are less potent than SARSCoV- 2. The inhibitors, however, showed decreased binding affinity to most of the mutant S-proteins than SARS-CoV-2, indicating it is more difficult to treat COVID using the therapeutic approach targeting the S-protein.

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