Docking Complexes of Active Phytochemicals with VK-deficient Genes

Abstract

Background:: Vitamin K (VK) deficiency occurs when the body does not have enough vitamin K to produce proteins that are essential for blood clotting and bone health. Vitamin K is a cofactor that plays a major role in various comorbidities. Over the years, efforts have been made to identify the interaction between natural compounds, such as K vitamers, that could play a sig-nificant role in regulation of the blood coagulation. We intended to obtain insights into the poten-tial therapeutic implications of phytochemicals for treating VK deficiency-related diseases by in-vestigating the interactions between phytochemicals and VK-deficient genes. Methods:: On active phytochemical docking complexes with VK-deficient genes, there is no spe-cific information available as of yet. In this computationally aided docking study, we were inter-ested in finding the pathogenic blood coagulation-related genes that are linked to VK deficiency. Based on literature reviews and databases, bioactive phytochemicals and other ligands were con-sidered. To provide precise predictions of ligand-protein interactions, docking parameters and scoring algorithms were thoroughly optimized. We have performed molecular docking studies and observed the way the complexes interact. Results:: Specific binding interactions between active phytochemicals and VK pathogenic muta-tions have been identified by the docking study. Hydrogen bonds, van der Waals interactions, and hydrophobic contacts, which are indications of high binding affinities, have been observed in the ligand-protein complexes. Few phytochemicals have demonstrated the ability to interact with the targets of VK-deficient genes, indicating their capacity to modify pathways relevant to VK defi-ciency. The results of the docking study have explained the three pathogenic genes, viz. VWF, F8, and CFTR, wherein VWF and F8 play important roles in blood coagulation and people with cyst-ic fibrosis, to have a deficiency in vitamin K. Thirty-five compounds from different plant and natural sources were screened through molecular docking, out of which two compounds have been considered as controls, including curcumin and warfarin (R-warfarin and S-warfarin), which are the most common anticoagulants readily available in the market. They act by inhibiting vita-min K epoxide reductase (VKOR), which is needed for the gamma-carboxylation of vitamin K-dependent factors. Conclusion:: A focus on other compounds, like theaflavin, ellagic acid, myricetin, and catechin was also made in this study as they show more binding affinity with the three pathogenic proteins. Based on the results, the complexes have been found to possess great potential and thus may be considered for further interaction studies. The potential for active phytochemicals to generate docking complexes with VK-deficient genes is highlighted in this computational analysis. Health disorders related to VK insufficiency may be significantly impacted by these interactions. To val-idate the expected interactions and determine the therapeutic potential of the identified phyto-chemicals, more experimental research, including in vitro and in vivo experiments, is needed. conclusion: In this study, the vitamers K and other drugs have been investigated in detail with three different pathogenic variants by AutoDock4 and have visualized the interactions with PyMOL. VWF, CFTR and F8 play a major role as blood coagulation in Vitamin K pathways. This in silico study of the pathogenic SNPs of VWF, CFTR and F8 targeted against 35 ligands among them five were considered important control ligands as S-warfarin, R-warfarin, and other ligands such as Theaflavine, Curcumin and Ellagic acid. Above all the ligands theaflavine and ellagic acid complexes that provides best high binding energies. Our findings will guide in the study of potential therapeutic inventions upon further experimental variant analysis in transcriptome studies. other: Docking studies proved that Inhibition of HEWL and Aβ42 fibril formation mediated by vitamin k3 can be initiated by interaction with proteolytically resistant or aggregate-prone regions (Alam et al., 2016). VK3 screened for potent inhibitory activity against SARS-CoV-2 3CL pro and the study targeted for developing antiviral agents (Wang et al., 2021). SARS-CoV-2 3CLpro is required for the conversion of viral polyproteins into mature non-structural proteins, making it a promising target for antiviral drug development. Vitamin K3, rather than Vitamin K1, K2, or K4, shows a significant inhibitory effect against SARS-CoV-2 3CLpro compared and screened with more than a thousand of chemicals. Then, to establish that Vitamin K3 could form a covalent connection with SARS-CoV-2 3CLpro, a time-dependent inhibitory experiment was performed. In our study, we have considered Phylloquinone (VK1), proteins were 6MSM (-4.94 kcal/mol) and 7KVE (-2.54 kcal/mol), both doesn’t have interacting residues but the Chain A of 7KWO interacting with ASN2118 (-3.97 kcal/mol) and the Chain B of 7KWO interacting with SER723 (-7.87kcal/mol). While interacting with the Menaquinone (VK2), the proteins of 7KVE (-2.70 kcal/mol) and the B chain of 7KWO (-5.70 kcal/mol) don't have interacting residues. However, the other proteins of 6MSM (-4.01 kcal/mol) and A Chain of 7KWO (-2.22 kcal/mol) interact with ASN2118. In comparing both VK1 and VK2, A chain of 7KWO interacting with the same residue of ASN2118. After that, the covalent interaction between Vitamin K3 and SARS-CoV-2 3CLpro was confirmed by further mass spectrometric analysis and molecular docking studies (Wang et al., 2021). The other study was done on Staphylococcus aureus which is a common source of hospital-acquired infections. The norA efflux pump is produced by the expression of the norA gene in the bacteria S. aureus. As a result, the goal of this work is to confirm the effect of menadione on efflux inhibition by inhibiting NorA pump gene expression and to examine the effects of menadione on bacterial membranes. In molecular docking, the presence of menadione causes a rise in fluorescence intensity. Menadione was found to interact with NorA residues ILE12, ILE15, PHE16, ILE19, PHE47, GLN51, ALA105, and MET109 in 100 percent of the clusters. In our study Menadione yielded -4.62 kcal/mol and interacting with ARG1739, ARG1621 in 7KVE; -4.37 kcal/mol (LEU1975, ALA1974) in Chain A of 7KWO ; -5.96 kcal/mol (GLN1069) in Chain B of 7KWO but the other protein 6MSM, the estimated inhibition constant is -4.31 kcal/mol and it doesn’t have interaction with any residues. The simulation studies revealed that numerous menadione molecules were able to pass through the bilayer, allowing water molecules to enter the bilayer's hydrophobic areas (Tintino et al., 2020). (Murad et al., 2022) studies the analysis of the structure and function of prospective therapeutic targets in metabolic pathways important for bacterial endurance, such as the vitamin K2 pathway. The experiment proved that designed peptides were produced and tested for their ability to inhibit S. aureus DHNA thioesterase (SaDHNA). The functional relevance of Asp16 and Glu31 for thioesterase activity and substrate binding at the putative active site was established by site-directed mutagenesis of SaDHNA. Future drug development and design research to limit the vitamin K2 production pathway will benefit from the high-resolution structure of SaDHNA and more information regarding substrate binding.Recently, (Czogalla et al., 2018) investigated the oral anticoagulants (OACs) to drug binding and verified putative interacting residues for both VKORC1 and VKORC1L1 and in-silico analysis have demonstrated the enzyme-specific differences in warfarin binding with lower OAC sensitivity. Warfarin acts as inhibitors of the vitamin K epoxide reductase (VKOR) and catalyzes the reduction of vitamin K quinone and vitamin K 2,3-epoxide, a process essential to sustain γ-carboxylation of vitamin K-dependent proteins. VKOR is also a therapeutic target of warfarin, and is used as anticoagulants to treat thrombotic disorders. Although warfarin is the most widely used anticoagulant, the mechanism and the structural and functional basis of vitamin K reduction by which warfarin inhibits its target remains unknown. (Czogalla et al., 2017) studied the challenge prevailing concept of noncompetitive warfarin inhibition because K vitamers and warfarin share binding sites on VKOR that include Phe55, a key residue binding either the substrate or inhibitor. The other study reveals that warfarin blocks a dynamic electron-transfer process in hVKOR. selectively inhibits this major cellular form of hVKOR, whereas disruption of the Cys51-Cys132 disulfide impairs warfarin binding and causes warfarin resistance and the structure simulations concluded that a closed warfarin-binding pocket stabilized by the Cys51-Cys132 linkage (Shen et al., 2017). The critical interactions involving Lys30, Phe55, and warfarin were less preferred in R-rats and VKOR-associated warfarin was more exposed to solvents. Additionally, a mutation of VKOR at position 76 results in a considerable increase in warfarin resistance (Takeda et al., 2021). The N-terminus of Tyr3 and the C terminus of Ser50, Gln53, Asp55, Glu57, and Ile59 are both essential for suppressing the activity of thrombin, according to the RDG-with hirudin's thrombin study (Huang et al., 2014). In comparing interacting residues with all the ligands of 6MSM protein, the following residues binding with the same ligands. THR1220, TYR1219, ASN1224 (Ellagic acid, Kaempferol and Ferulic acid); TYR304, SER308 (Theaflavin, Quercitrin); PHE405 (Catechol, shikimic acid); SER308 (Sinapic acid, Heparin); ASN1224 (Gallic acid, coumaric acid).