Comparative MD Study of Inhibitory Activity of Opaganib and Adamantane‐Isothiourea Derivatives toward COVID‐19 Main Protease M^pro

Abstract

In this study, the inhibitory potency of four adamantlyisothiourea derivatives (compounds 1 [4-bromobenzyl (Z)-N'-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidate], 2 [3,5-bis(trifluoromethyl)benzyl (Z)-N'-(adamantan-1-yl)-4-phenylpiperazine-1-carbothioimidate], 3 [4-bromobenzyl (Z)-N-(adamantan-1-yl)morpholine-4-carbothioimidate] and 4 [3,5-bis (trifluoromethyl)benzyl (Z)-N-(adamantan-1-yl)morpholine-4carbothioimidate]) was evaluated against SARS-CoV-2 targeted proteins. The investigated compounds 1-4 possess a similar structure to opaganib, which is used in studies like a potential drug for COVID-19 treatment. Since examined adamantlyisothiourea derivatives (1-4) shown broad-spectrum of antibacterial activity and significant in vitro cytotoxic effects against five human tumor cell lines and shown similarity in structure with opaganib, it was of interest to study their inhibitory potency toward some SARS-CoV-2 proteins such as SARS-CoV-2 main protease M pro and mutation of SARS-CoV-2 Spike (S) Protein D614G. The inhibitory potency of studied compounds is examined using molecular docking and molecular dynamic simulations. The results of molecular docking simulations indicate compound 1 as the most prominent candidate of inhibition of SARS-CoV-2 main protease M pro (~G bind = 11.24 kcal/mol), while almost the same inhibition potency of all studied compounds is exhibited toward D614G. Regarding the results obtained by molecular dynamic simulations, compounds 1 and 4 possess similar inhibitory potency toward SARS-CoV-2 main protease M pro as opaganib (~G bind �40 kcal/mol).

Nascent pharmacological advancement in adamantane derivatives

“…Jovanović et al [143] 85 HsEH, RsEH, MsEH (IC 50 0.4 nM each) Chloro group on adamantane moiety enhanced the activity.…”

“…Jovanović et al have synthesized a novel class of adamantane hybrids containing isothiourea moiety and screened for their inhibitory activity against coronavirus disease 2019 (COVID‐19) main protease Mpro using a molecular docking technique. [ 143 ] Hybrid 84 displayed better potency than the reference opaganib. Codony et al have reported the synthesis of benzohomoadamantane hybrids and assessed in vivo inhibitory activities against human, rat, and murine sEH.…”

Antiviral activities of natural compounds and ionic liquids to inhibit the Mpro of SARS-CoV-2: a computational approach

“… 19,20 Recently, Marković and his co-workers studied, adamantane-isothiourea derivatives have strong inhibition potency towards Mpro and mutation of SARS-CoV-2 Spike protein D614G. 21 Coumarin derivatives and their Pd( ii ) complexes have stronger binding affinity with Mpro of SARS-CoV-2 compared to the FDA approved drugs. 22 These studies explored that natural compounds and their derivatives potent inhibitors for Mpro of SARS-CoV-2.…”