Computer simulation of the processes of complexation between new derivatives of quinazoline-4(3H)-one, quinazoline-2,4(1H,3H)-dione and cytochrome P-450 sterol-7Α-hydroxylase (CYP27A1) when studying their antimicrobial effects against Klebsiella pneumoniae

Introduction. Multi-resistance of Klebsiella pneumoniae to known antimicrobial agents determines the need for urgent development of new drugs exhibiting an antibacterial effect. Compounds used in the treatment of non-infectious pathologies, affecting various protein targets and realizing the "antimicrobial potential", seem promising in the search for new derivatives. Of particular interest is the predicted high probability of inhibition of sterol-27-hydroxylase cytochrome P-450 (CYP27A1) by new derivatives of quinazoline-4(3H)-one and quinazoline-2,4(1H,3H)-dione with the possibility of preventing the processes of conversion of cholesterol, as the main component of macrophage lipid rafts on which pathogen adhesion occurs. Activation of phagocytosis, as well as disruption of the formation of the polysaccharide capsule of K. pneumoniae, is considered one of the probable mechanisms of the antibacterial effect of the studied substances.

The aim – determination of reactivity parameters and potential pharmacological activity of quinazolin-4(3H)-one and quinazolin-2,4(1H,3H)-dione derivatives; prediction of the mechanism of antimicrobial action of new quinazolinones against K. pneumoniae based on the formation of a complex with CYP27A1.

Material and methods. The probability of CYP27A1 inhibition by new quinazolinone derivatives was predicted using the PASS program. Quantum chemical parameters were calculated using the parameterized PM7 method in the MOPAC 2016 program. The structural characteristics of the studied substances were determined using ProTox 3.0. Some pharmacokinetic parameters were assessed using the admetSAR software tool. A three-dimensional model of the protein structure of CYP27A1 was generated on the AlphaFold platform; optimal conformation and further clustering of protein sequences using the MMseqs2 and Foldseek algorithms. The determination of the energy parameters of the intermolecular complexes “quinazolinone CYP27A1”, as well as the identification of the amino acid sites to which the quinzolinone derivative binds, was carried out using the Swiss Dock system.

Results. Quantum-chemical and structural parameters of quinazoline-4(3H)-one and quinazoline-2,4(1H,3H)-dione derivatives, as well as their intermolecular complexes with CYP27A1, were established, and some pharmacokinetic parameters of the studied substances were predicted.

Conclusions. Control of the interaction of the compound with the lipid raft of the macrophage and an increase in the degree of penetration of the pathogen into its cell can be considered as a probable mechanism of the antibacterial action of quinazoline-4(3H)-one and quinazoline-2,4(1H,3H)-dione derivatives against Klebsiella pneumoniae. An increase in the number of naphthyl radicals in their molecule leads to a decrease in reactivity. Naphthyl radicals do not act as a pharmacophore of antimicrobial action against K. pneumoniae.