Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10

Li, Zhe; Huang, Yi‐You; Wu, Yinuo; Chen, Jingyi; Wu, Deyan; Zhan, Chang‐Guo; Luo, Hai‐Bin

doi:10.1021/acs.jmedchem.8b01763

Cited by 64 publications

(93 citation statements)

References 56 publications

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“…MD simulations trajectories of complex system were used to determined relative change in binding free energy according to the MM-GBSA method [ 53 , 54 , 55 , 56 ]. In order to calculate binding free energies like for CMPD178-nsP3 of CHIKV, nsP3 of CHIKV and CMPD178 was calculated for high accuracy results [ 23 , 57 ].…”

Section: Methodsmentioning

confidence: 99%

In-silico prediction of novel drug-target complex of nsp3 of CHIKV through molecular dynamic simulation

Kumar

Meena

Kumari

et al. 2020

Heliyon

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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.

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Section: Methodsmentioning

confidence: 99%

In-silico prediction of novel drug-target complex of nsp3 of CHIKV through molecular dynamic simulation

Kumar

Meena

Kumari

et al. 2020

Heliyon

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show abstract

“…In order to obtain the binding pattern and calculate the binding free energy between DIP and Mpro, DIP was firstly docked onto Mpro by using Glide-SP method with the default parameters 47 , and the optimal binding pose ( Fig. S1) was further assessed by absolute binding free energy calculation with free energy perturbation 48 . The calculations were carried out in Gromacs 2019 49 , and the thermodynamic cycle and procedure was similar to that used by Matteo et al 50 .…”

Section: Free Energy Perturbation Predictionmentioning

confidence: 99%

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19

Liu

et al. 2020

Acta Pharmaceutica Sinica B

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Graphical abstractDipyridamole bound to the SARS-CoV-2 protease Mpro after identified via the virtual screening and bioassay validation, and thus suppressed viral replication in vitro. As a result, dipyridamole supplementation was associated with significantly decreased concentrations of D-dimers, increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients.Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction.Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with Corona Virus Disease 2019 , we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. Food and Drug Administration (FDA) approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P<0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.

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“…For the virtual screening to identify new hits or leads, it is necessary to predict absolute binding free energy (ABFE) for each ligand binding with the target without the requirement to use any reference ligand structure. The FEP-ABFE approach has the advantage of predicting binding affinities between ligands and their targets more accurately than conventional computational methods, such as pharmacophore, molecule docking, and molecular simulations (29)(30)(31). However, the previously used FEP-ABFE calculations are extremely expensive and time consuming and, thus, not suitable for virtual screening purposes (that required to screen a large number of compounds) (32,33).…”

Section: Significancementioning

confidence: 99%

Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

Huang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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195

169

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The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and thus repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a restraint energy distribution (RED) function, making the practical FEP-ABFE−based virtual screening of the existing drug library possible. As a result, out of 25 drugs predicted, 15 were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (inhibitory constant Ki = 0.04 µM) which has shown promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki = 0.36 µM) and chloroquine (Ki = 0.56 µM) were also found to potently inhibit SARS-CoV-2 Mpro. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts.

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Absolute Binding Free Energy Calculation and Design of a Subnanomolar Inhibitor of Phosphodiesterase-10

Cited by 64 publications

References 56 publications

In-silico prediction of novel drug-target complex of nsp3 of CHIKV through molecular dynamic simulation

In-silico prediction of novel drug-target complex of nsp3 of CHIKV through molecular dynamic simulation

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19

Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs

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