Abstract:Selective docking is a novel concept for drug designing and currently used to find potential inhibitors against a nonstructural polyprotein (nsP2) of the chikungunya virus (CHIKV). Herein, authors designed a library of 200 molecules based on pyranooxazoles and used virtual screening, docking, isothermally and non-isothermally MD simulations and free energy calculations to get potential candidates. The computational strategy is significant to find the promising inhibitor against this infection. Molecular dockin… Show more
“…In silico methods are being explored by the researchers due to the efficiency and strategic approach. Computational tools are used to create a library and filtering them to get the biological potent compound against a receptor [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. In this work, authors have designed a multi-component reaction (MCR) to produce pyrazolophthalazine via the one pot reaction between benzaldehyde, 2,3-dihydrophthalazine-1,4-dione and oxazolidine-2,4-dione (OZD) and its feasibility was studied through DFT method using Gaussian 09.…”
Literature reported that nsp3 of CHIKV is an important target for the designing of drug as it involves in the replication, survival etc. Herein, about eighteen million molecules available in the ZINC database are filtered against nsp3 using RASPD. Top five hit drug molecules were then taken from the total screened molecules (6988) from ZINC database. Then, a one pot-three components reaction is designed to get the pyrazolophthalazine and its formation was studied using DFT method. Authors created a library of 200 compounds using the product obtained in the reaction and filtered against nsp3 of CHIKV based on docking using iGEMDOCK, a computational tool. Authors have studied the best molecules after applying the the Lipinski's rule of five and bioactive score. Further, the authors took the best compound i.e. CMPD178 and performed the MD simulations and tdMD simulations with nsp3 protease using AMBER18. MD trajectories were studied to collect the information about the nsp3 of CHIKV with and without screened compound and then, MM-GBSA calculations were performed to calculate change in binding free energies for the formation of complex. The aim of the work is to find the potential candidate as promising inhibitor against nsp3 of CHIKV.
“…In silico methods are being explored by the researchers due to the efficiency and strategic approach. Computational tools are used to create a library and filtering them to get the biological potent compound against a receptor [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. In this work, authors have designed a multi-component reaction (MCR) to produce pyrazolophthalazine via the one pot reaction between benzaldehyde, 2,3-dihydrophthalazine-1,4-dione and oxazolidine-2,4-dione (OZD) and its feasibility was studied through DFT method using Gaussian 09.…”
Literature reported that nsp3 of CHIKV is an important target for the designing of drug as it involves in the replication, survival etc. Herein, about eighteen million molecules available in the ZINC database are filtered against nsp3 using RASPD. Top five hit drug molecules were then taken from the total screened molecules (6988) from ZINC database. Then, a one pot-three components reaction is designed to get the pyrazolophthalazine and its formation was studied using DFT method. Authors created a library of 200 compounds using the product obtained in the reaction and filtered against nsp3 of CHIKV based on docking using iGEMDOCK, a computational tool. Authors have studied the best molecules after applying the the Lipinski's rule of five and bioactive score. Further, the authors took the best compound i.e. CMPD178 and performed the MD simulations and tdMD simulations with nsp3 protease using AMBER18. MD trajectories were studied to collect the information about the nsp3 of CHIKV with and without screened compound and then, MM-GBSA calculations were performed to calculate change in binding free energies for the formation of complex. The aim of the work is to find the potential candidate as promising inhibitor against nsp3 of CHIKV.
“…Molecular docking is an interesting approach to understand the interaction of the designed molecules with the proteases of the target. The molecular docking is based on the algorithms to study the interaction based on the binding energy (Durgesh et al, 2020;Kumar et al, 2020aKumar et al, , 2020cSingh et al, 2019;Vishvakarma, Shukla, et al, 2019;. Molecular docking between the designed molecules with the main protease of the SARS-CoV-2 and Figure 2.…”
Section: Molecular Docking Of the Designed Conjugates Of Noscapine Wimentioning
First case of the present epidemic, coronavirus disease (COVID-19) is reported in the Wuhan, a city of the China and all the countries throughout the world are being affected. COVID-19 is named by World Health Organization and it stands for coronavirus disease-19. As on 27 th October, 2020, 73,776,588 people around the world are infected. It is also known as SARS-CoV-2 infection. Till date, there is no promising drug or vaccine available in market to cure from this lethal infection. As the literature reported that noscapine a promising candidate to cure from malaria as well reported to be cough suppressant and anti-cancerous. In our previous work, a derivative of noscapine has shown potential behavior against the main protease of novel coronavirus or SARS-CoV-2. Based on the previous study, hybrid molecules based on noscapine and repurposing (antiviral) drugs were designed to target the main protease of novel coronavirus and falcipan-2 using molecular docking. It is proposed that the designed hydrids or conjugates may have promising antiviral property i.e. against the main protease of novel coronavirus and falcipan-2. The designed molecules were thoroughly studied by DFT and different thermodynamic parameters were determined. Further, infrared and Raman spectra of the designed hybrid molecules were determined and studied.
Graphical abstract
In December, 2019, the SARS-CoV-2 was reported for the first time and the infected person is reported at Wuhan, China. Till date, about twenty four million people around the world are infected due to the SARS-CoV-2. The structure of this corona virus is new and different from other corona viruses. The genome has a positive sense single RNA strand and it is responsible for the encoding of the protein. The protease of the SARS-CoV-2 is responsible for the cleavage and therefore, it should be targeted to develop medicine. Till date, no medicine or vaccine is in the market to cure from the infection. Researchers around the world are working on the development of efficacious and safe vaccine/ drug to cure from the infection. Therefore, the authors used previously synthesized compounds, xanthene-triazole-chloroquinoline/ xanthene-chloroquinoline hybrids for the inhibition of the main protease of the SARS-CoV-2 via using computational tools, molecular docking and ADMET properties.
COMD AP3
was found to be the best candidate from the library of the designed molecules. It has acceptable solubility along with the distribution and metabolism property. ADMET results corroborate the docking result towards the potency of
COMP AP3
.
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