RESUMEN
The hunt for potential lead/drug molecules from different resources, especially from natural resources, for possible treatment of COVID-19 is ongoing. Several compounds have already been identified, but only a few are good enough to show potential against the virus. Among the identified druggable target proteins of SARS-CoV-2, this study focuses on non-structural RNA-dependent RNA polymerase protein (RdRp), a well-known enzyme for both viral genome replication and viral mRNA synthesis, and is therefore considered to be the primary target. In this study, the virtual screening followed by an in-depth docking study of the Compounds Library found that natural compound Cyclocurcumin and Silybin B have strong interaction with RdRp and much better than the remdesivir with free binding energy and inhibition constant value as êzÅ-6.29 kcal/mol and 58.39 µMêzÅ, and êzÅ-7.93kcal/mol and 45.3 µMêzÅ, respectively. The finding indicated that the selected hits (Cyclocurcumin and Silybin B) could act as non-nucleotide anti-polymerase agents, and can be further optimized as a potential inhibitor of RdRp by benchwork experiments.
Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/metabolismo , Productos Biológicos/metabolismo , COVID-19/metabolismo , ARN Polimerasa Dependiente de ARN de Coronavirus/metabolismo , Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular/métodos , Fitoquímicos/metabolismo , SARS-CoV-2/enzimología , Adenosina Monofosfato/química , Adenosina Monofosfato/metabolismo , Alanina/química , Alanina/metabolismo , Antivirales/química , Productos Biológicos/química , COVID-19/virología , Dominio Catalítico , ARN Polimerasa Dependiente de ARN de Coronavirus/antagonistas & inhibidores , ARN Polimerasa Dependiente de ARN de Coronavirus/química , Curcumina/análogos & derivados , Curcumina/química , Curcumina/metabolismo , Bases de Datos de Proteínas , Evaluación Preclínica de Medicamentos/métodos , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Fitoquímicos/química , Unión Proteica , Silibina/química , Silibina/metabolismoRESUMEN
The integration of calcium and a p53-Mdm2 oscillator model is studied using a deterministic as well as a stochastic approach, to investigate the impact of a calcium wave on single cell dynamics and on the inter-oscillator interaction. The high dose of calcium in the system activates the nitric oxide synthase, synthesizing nitric oxide which then downregulates Mdm2 and influences drastically the p53-Mdm2 network regulation, lifting the system from a normal to a stressed state. The increase in calcium level switches the system to different states, as identified by the different behaviours of the p53 temporal dynamics, i.e. oscillation death to sustain the oscillation state via a mixed state of dampened and oscillation death states. Further increase of the calcium dose in the system switches the system from sustained to oscillation death state again, while an excess of calcium shifts the cell to an apoptotic state. Another important property of the calcium ion is its ability to behave as a synchronizing agent among the interacting systems. The time evolution of the p53 dynamics of the two diffusively coupled systems at stress condition via Ca(2+) shows synchronization between the two systems. The noise contained in the system interestingly helps the system to maintain its stabilized state (normal condition). However, noise has the tendency to destruct the synchronization effect, which means that it tries to restrict the system from external signals to maintain its normal condition. However, at the stress condition, the synchronization rate is found to be faster.