Computational study of the therapeutic potentials of a new series of imidazole derivatives against SARS-CoV-2

Abstract

Owing to the urgent need for therapeutic intervention against the SARS-coronavirus 2 (SARS-CoV-2) pandemic, we employed an in silico approach to evaluate the SARS-CoV-2 inhibitory potential of newly synthesized imidazoles. The inhibitory potential of the compounds against SARS-CoV-2 drug targets - main protease (Mpro), spike protein (Spro) and RNA-dependent RNA polymerase (RdRp) were investigated through molecular docking analysis. The binding free energy of the protein-ligand complexes were estimated, pharmacophore models were generated and the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of the compounds were determined. The compounds displayed various levels of binding affinities for the SARS-CoV-2 drug targets. Bisimidazole C2 scored highest against all the targets, with its aromatic rings including the two imidazole groups contributing to the binding. Among the phenyl-substituted 1H-imidazoles, C11 scored highest against all targets. C15 scored highest against Spro and C16 against Mpro and RdRp among the thiophene-imidazoles. The compounds interacted with HIS 41 - CYS 145 and GLU 288 – ASP 289 – GLU 290 of Mpro, ASN 501 of Spro receptor binding motif and some active site amino acids of RdRp. These novel imidazole compounds could be further developed as drug candidates against SARS-CoV-2 following lead optimization and experimental studies.

Computational Study of the Therapeutic Potential of Novel Heterocyclic Derivatives against SARS-CoV-2

“…This could be linked to the presence of the delocalized пelectrons in the aromatic ring and the presence of polar compounds in the structure of these compounds. Approximately 20% of essential amino acids are structurally aromatic; interactions involving aromatic compounds are essential to biological recognition, including protein-ligand interaction [9]. Singh [57] reported that aromatic compounds are crucial in drug design as they engender improved efficacy and lead to optimization of the drug.…”

“…A high-quality drug candidate should be effective against the therapeutic target and have appropriate ADMET properties at a therapeutic dose [65]. As a result, many in silico models for predicting chemical ADMET properties have been created and it has become advantageous as it reveals a pharmacokinetics-related failure of drugs before proceeding to the clinical phase [9].…”

“…COVID 2021, 1 758 SARS-CoV-2, including the recently reported severe variant B.1.617.2 [7,8], attacks the respiratory tract with symptoms ranging from breathing difficulties, sore throat, high fever, diarrhea, and cough to multiple organ failure and ultimately death [9]. This can occur when the spike protein (Spro), which possesses an S1 domain and an S2 subunit, binds to angiotensin-converting enzyme-2 (ACE-2) receptors on the surface of the host alveoli to allow for entry [10].…”

Identification of Possible Inhibitors of SARS-CoV-2 Main Protease From Some Bioactive Compounds of Artemisia Annua: An in Silico Approach

“…The PHASE module of the Schrödinger Suite 2020-3 was used to generate an auto/e-pharmacophore model as previously described 54 . The process was set to generate a maximum of 7 features at a minimum feature-feature distance of 2.00 and the minimum distance between features of the same type was set at 4.00 and donors were set as vectors.…”

Identification of lead compounds from large natural product library targeting 3C-like protease of SARS-CoV-2 using E-pharmacophore modelling, QSAR and molecular dynamics simulation

“…Using in silico studies, many small molecular weight compounds including the existing FDA-approved drugs have proven to be promising therapeutics against 3CL pro of SARS-CoV-2 (Li et al 2020a , b ; Wei-chung et al 2021 ; Johnson et al 2021 ; Al-Bustany et al 2021 ). Some of these compounds have been validated using experimental studies, and they showed considerable inhibitory prowess (pIC50) against 3CL pro of SARS-CoV-2.…”