Dataset Information

Discovering potent inhibitors against the Mpro of the SARS-CoV-2. A medicinal chemistry approach

ABSTRACT: The global pandemic caused by a single-stranded RNA (ssRNA) virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still at its peak, with new cases being reported daily. Although the vaccines have been administered on a massive scale, the frequent mutations in the viral gene and resilience of the future strains could be more problematic. Therefore, new compounds are always needed to be available for therapeutic approaches. We carried out the present study to discover potential drug compounds against the SARS-CoV-2 main protease (Mpro). A total of 16,000 drug-like small molecules from the ChemBridge database were virtually screened to obtain the top hits. As a result, 1032 hits were selected based on their docking scores. Next, these structures were prepared for molecular docking, and each small molecule was docked into the active site of the Mpro. Only compounds with solid interactions with the active site residues and the highest docking score were subjected to molecular dynamics (MD) simulation. The post-simulation analyses were carried out using the in-built GROMACS tools to gauge the stability, flexibility, and compactness. Principal component analysis (PCA) and hydrogen bonding were also calculated to observe trends and affinity of the drugs towards the target. Among the five top compounds, C1, C3, and C6 revealed strong interaction with the target's active site and remained highly stable throughout the simulation. We believe the predicted compounds in this study could be potential inhibitors in the natural system and can be utilized in designing therapeutic strategies against the SARS-CoV-2. Graphical abstract Image 1

SUBMITTER: Mehmood A

PROVIDER: S-EPMC8789387 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The worldwide pandemic of coronavirus disease 2019 (COVID-19) along with the various newly discovered major SARS-CoV-2 variants, including B.1.1.7, B.1.351, and B.1.1.28, constitute the Variant of Concerns (VOC). It's difficult to keep these variants from spreading over the planet. As a result of these VOCs, the fifth wave has already begun in several countries. The rapid spread of VOCs is posing a serious threat to human civilization. There is currently no specific medicine available for the treatment of COVID-19. Here, we present the findings of methods that used a combination of structure-assisted drug design, virtual screening, and high-throughput screening to swiftly generate lead compounds against Mpro protein of SARs-CoV-2. Therapeutics, in addition to vaccinations, are an essential element of the healthcare response to COVID-19's persistent threat. In the current study, we designed the efficient compounds that may combat all emerging variants of SARs-CoV-2 by targeting the common Mpro protein. The present study was aimed to discover new compounds that may be proposed as new therapeutic agents to treat COVID-19 infection without any adverse effects. For this purpose, a computational-based virtual screening of 352 in-house synthesized compounds library was performed through molecular docking and Molecular Dynamics (MD) simulation approach. As a result, four novel potent compounds were successfully shortlisted by implementing certain pharmacological, physiological, and ADMET criteria i.e., compounds 3, 4, 21, and 22. Furthermore, MD simulations were performed to evaluate the stability and dynamic behavior of these compounds with Mpro complex for about 30 ns. Eventually, compound 22 was found to be highly potent against Mpro protein and was further evaluated by applying 100 ns simulations. Our findings showed that these shortlisted compounds may have potency to treat the COVID-19 infection for which further experimental validation is proposed as part of a follow-up investigation.

Project description:The emergence of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) with the most contagious variants, alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2), and Omicron (B.1.1.529) has continuously added a higher number of morbidity and mortality, globally. The present integrated bioinformatics-cheminformatics approach was employed to locate potent antiviral marine alkaloids that could be used against SARS-CoV-2. Initially, 57 antiviral marine alkaloids and two repurposing drugs were selected from an extensive literature review. Then, the putative target enzyme SARS-CoV-2 main protease (SARS-CoV-2-Mpro) was retrieved from the protein data bank and carried out a virtual screening-cum-molecular docking study with all candidates using PyRx 0.8 and AutoDock 4.2 software. Further, the molecular dynamics (MD) simulation of the two most potential alkaloids and a drug docking complex at 100 ns (with two ligand topology files from PRODRG and ATB server, separately), the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) free energy, and contributions of entropy were investigated. Then, the physicochemical-toxicity-pharmacokinetics-drug-likeness profiles, the frontier molecular orbitals energies (highest occupied molecular orbital, lowest unoccupied molecular orbital, and ΔE), and structural-activity relationship were assessed and analyzed. Based on binding energy, 8-hydroxymanzamine (-10.5 kcal/mol) and manzamine A (-10.1 kcal/mol) from all alkaloids with darunavir (-7.9 kcal/mol) and lopinavir (-7.4 kcal/mol) against SARS-CoV-2-Mpro were recorded. The MD simulation (RMSD, RMSF, Rg, H-bond, MM/PBSA binding energy) illustrated that the 8-hydroxymanzamine exhibits a static thermodynamic feature than the other two complexes. The predicted physicochemical, toxicity, pharmacokinetics, and drug-likeness profiles also revealed that the 8-hydroxymanzamine could be used as a potential lead candidate individually and/or synergistically with darunavir or lopinavir to combat SARS-CoV-2 infection after some pharmacological validation.

Dataset Information

Discovering potent inhibitors against the Mpro of the SARS-CoV-2. A medicinal chemistry approach

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets