The effect of various compounds on the COVID mechanisms, from chemical to molecular aspects

Abstract

The novel coronavirus that caused COVID-19 pandemic is SARS-CoV-2. Although various vaccines are currently being used to prevent the disease's severe consequences, there is still a need for medications for those who become infected. The SARS-CoV-2 has a variety of proteins that have been studied extensively since the virus's advent. In this review article, we looked at chemical to molecular aspects of the various structures studied that have pharmaceutical activity and attempted to find a link between drug activity and compound structure. For example, designing of the compounds which bind to the allosteric site and modify hydrogen bonds or the salt bridges can disrupt SARS-CoV2 RBD-ACE2 complex. It seems that quaternary ammonium moiety and quinolin-1-ium structure could act as a negative allosteric modulator to reduce the tendency between spike-ACE2. Pharmaceutical structures with amino heads and hydrophobic tails can block envelope protein to prevent making mature SARS-CoV-2. Also, structures based on naphthalene pharmacophores or isosteres can form a strong bond with the PLpro and form a π-π and the Mpro's active site can be occupied by octapeptide compounds or linear compounds with a similar fitting ability to octapeptide compounds. And for protein RdRp, it is critical to consider pH and pKa so that pKa regulation of compounds to comply with patients is very effective, thus, the presence of tetrazole, phenylpyrazole groups, and analogs of pyrophosphate in the designed drugs increase the likelihood of the RdRp active site inhibition. Finally, it can be deduced that designing hybrid drug molecules along with considering the aforementioned characteristics would be a suitable approach for developing medicines in order to accurate targeting and complete inhibition this virus.

Keywords: 3Clpro; COVID-19; PLpro; RdRp; SARS-CoV-2; Spike-ACE2.

Graphical abstract

Fig. 1

The life cycle of SARS-CoV-2 virus in a human cell.

Fig. 2

Regulation of spike-ACE2 by binding a negative allosteric modulator at the allosteric site of ACE2.

Fig. 3

Structures of amantadine, HMA, Nocardamine, and Desferrioxamine as the best structures to inhibit envelope protein of SARS-CoV-2.

Fig. 4

The reaction mechanism between the Thiolate anion of the catalytic Cys145 and the chloromethyl ketone moiety of CMK.

Fig. 5

The reaction mechanism between catalytic Cys145 and Cm–FF–H.

Fig. 6

The reaction mechanism between Plpro and Afatinib Michael's acceptor group.

Fig. 7

A chemical reaction between peptidyl boronic acid and serine residues in Plpro.

Fig. 8

The chemical reaction between electrophilic nitriles in nitrile-containing and serine and cysteine moiety.

Fig. 9

The chemical reaction mechanism between Zn-ejector drug and catalytic cysteines.

Fig. 10

The reaction mechanism between His-Cys catalytic dyad with substrates.

Fig. 11

The α-ketoamide reactive warheads are present in potent SARS-CoV-2 Mpro inhibitors.

Fig. 12

Fluoromethyl ketones, Aziridinyl Peptide and Aza-peptide Epoxide that react with nucleophilic amino acids within the active site of proteases.

Fig. 13

The reaction mechanism between vinyl sulfone and thiol moiety of cystein group.

Fig. 14

The reaction between fluorinated ketone and Ser-OH or Cys-SH to form a thermodynamically stable hemiketal or hemithioketal after nucleophilic attack.

Fig. 15

The synthetic strategy to produce the main protease (Mpro) inhibitors of SARS-CoV-2.

Fig. 16

Alkylation of the active site cysteine and then the ring-opening reaction of epoxy ketones.

Fig. 17

The mechanism of action of Ritonavir and Lopinavir.

Fig. 18

Similar replacement of carboxylic acid with triazole.

Fig. 19

Molnupiravir tautomers (keto-oxime, keto-hydroxylamine, and hydroxyl-oxime) and its itramolecular hydrogen bonding.

Fig. 20

The chemical structure of baricitinib and its pyrrolopyrimidine moiety.

Fig. 21

Design of nirmatrelvir instead of water-soluble phosphate prodrug i.e. Lufotrelvir.