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CONTEXT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 infection and responsible for millions of victims worldwide, remains a significant threat to public health. Even after the development of vaccines, research interest in the emergence of new variants is still prominent. Currently, the focus is on the search for effective and safe drugs, given the limitations and side effects observed for the synthetic drugs administered so far. In this sense, bioactive natural products that are widely used in the pharmaceutical industry due to their effectiveness and low toxicity have emerged as potential options in the search for safe drugs against COVID-19. Following this line, we screened 10 bioactive compounds derived from cholesterol for molecules capable of interacting with the receptor-binding domain (RBD) of the spike protein from SARS-CoV-2 (SC2Spike), responsible for the virus's invasion of human cells. Rounds of docking followed by molecular dynamics simulations and binding energy calculations enabled the selection of three compounds worth being experimentally evaluated against SARS-CoV-2. METHODS: The 3D structures of the cholesterol derivatives were prepared and optimized using the Spartan 08 software with the semi-empirical method PM3. They were then exported to the Molegro Virtual Docking (MVD®) software, where they were docked onto the RBD of a 3D structure of the SC2Spike protein that was imported from the Protein Data Bank (PDB). The best poses obtained from MVD® were subjected to rounds of molecular dynamics simulations using the GROMACS software, with the OPLS/AA force field. Frames from the MD simulation trajectories were used to calculate the ligand's free binding energies using the molecular mechanics - Poisson-Boltzmann surface area (MM-PBSA) method. All results were analyzed using the xmgrace and Visual Molecular Dynamics (VMD) software.
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Productos Biológicos , COVID-19 , Humanos , SARS-CoV-2 , Productos Biológicos/farmacología , Simulación de Dinámica Molecular , Bases de Datos de Proteínas , Simulación del Acoplamiento Molecular , Antivirales/farmacologíaRESUMEN
In the present work, a library of 239 frentizole derivatives formerly synthesized by our research group were virtually screened on the FRB domain of mTOR in a search of potential binders for further experimental evaluation. 39 compounds from this library were virtually selected and classified in 7 groups according to their structural features. 9 representative compounds of these 7 groups were further submitted to rounds of MD simulation and MM-PBSA calculations. Analysis of our results pointed to the most promising among these groups as binders to the FRB domain of mTOR. We believe that they structurally represent a priority portion of the original library for further experimental evaluation.
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Simulación de Dinámica Molecular , Serina-Treonina Quinasas TOR , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The misuse of novichok agents in assassination attempts has been reported in the international media since 2018. These relatively new class of neurotoxic agents is claimed to be more toxic than the agents of the G and V series and so far, there is no report yet in literature about potential antidotes against them. To shed some light into this issue, we report here the design and synthesis of NTMGMP, a surrogate of A-242 and also the first surrogate of a novichok agent useful for experimental evaluation of antidotes. Furthermore, the efficiency of the current commercial oximes to reactivate NTMGMP-inhibited acetylcholinesterase (AChE) was evaluated. The Ellman test was used to confirm the complete inhibition of AChE, and to compare the subsequent rates of reactivation in vitro as well as to evaluate aging. In parallel, molecular docking, molecular dynamics and MM-PBSA studies were performed on a computational model of the human AChE (HssAChE)/NTMGMP complex to assess the reactivation performances of the commercial oximes in silico. Experimental and theoretical studies matched the exact hierarchy of efficiency and pointed to trimedoxime as the most promising commercial oxime for reactivation of AChE inhibited by A-242.
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Reactivadores de la Colinesterasa , Agentes Nerviosos , Acetilcolinesterasa , Antídotos/farmacología , Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa/farmacología , Humanos , Simulación del Acoplamiento Molecular , Agentes Nerviosos/toxicidad , Oximas/farmacologíaRESUMEN
Ricin is a potent cytotoxin with no available antidote. Its catalytic subunit, RTA, damages the ribosomal RNA (rRNA) of eukaryotic cells, preventing protein synthesis and eventually leading to cell death. The combination between easiness of obtention and high toxicity turns ricin into a potential weapon for terrorist attacks, urging the need of discovering effective antidotes. On this context, we used computational techniques, in order to identify potential ricin inhibitors among approved drugs. Two libraries were screened by two different docking algorithms, followed by molecular dynamics simulations and MM-PBSA calculations in order to corroborate the docking results. Three drugs were identified as potential ricin inhibitors: deferoxamine, leucovorin and plazomicin. Our calculations showed that these compounds were able to, simultaneously, form hydrogen bonds with residues of the catalytic site and the secondary binding site of RTA, qualifying as potential antidotes against intoxication by ricin.Communicated by Ramaswamy H. Sarma.
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Ricina , Antídotos , Reposicionamiento de Medicamentos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Ricina/química , Ricina/metabolismo , Ricina/farmacologíaRESUMEN
The acute respiratory syndrome caused by the SARS-CoV-2, known as COVID-19, has been ruthlessly tormenting the world population for more than six months. However, so far no effective drug or vaccine against this plague have emerged yet, despite the huge effort in course by researchers and pharmaceutical companies worldwide. Willing to contribute with this fight to defeat COVID-19, we performed a virtual screening study on a library containing Food and Drug Administration (FDA) approved drugs, in a search for molecules capable of hitting three main molecular targets of SARS-CoV-2 currently available in the Protein Data Bank (PDB). Our results were refined with further molecular dynamics (MD) simulations and MM-PBSA calculations and pointed to 7 multi-target hits which we propose here for experimental evaluation and repurposing as potential drugs against COVID-19. Additional rounds of docking, MD simulations and MM-PBSA calculations with remdesivir suggested that this compound can also work as a multi-target drug against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
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Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Proteasas 3C de Coronavirus , Cisteína Endopeptidasas , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Preparaciones Farmacéuticas , Inhibidores de ProteasasRESUMEN
Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.