In Silico Design Of Novel Ester-Based Derivatives As Nephroprotective Potential: Molecular Docking And Pharmacokinetic Evaluation

Nephrotoxicity includes a number of disorders, including acute renal failure, CKD progression, renal tubular injury, and glomerular damage. It is a critical medical concern since it causes hospitalization, higher healthcare expenses, and death worldwide.^[1] Antibiotics such as aminoglycosides,^[2] amphotericin B,^[3] beta-lactams,^[4] cephaloridine, cephaloglycin, ^[9] imipenem,^[5] quinolones,^[6] vancomycin,^[4,7] and rifampin ^[8] are examples of classical nephrotoxins.^[9] The following pathways, including NF-kB and TNF alpha, also activate pro-inflammatory cytokines, resulting in oxidative stress and cellular apoptosis, as well as kidney injury.^[10] Drug-induced nephrotoxicity can affect the glomerulus, tubular epithelium, interstitial tissues, and blood vessels in the renal vascular bed. Several processes have been attributed to the development of nephropathy in these illnesses, including changes in renal hemodynamic, direct tubule toxicity, inflammation, crystal formation, rhabdomyolysis, and thrombotic microangiopathy.^[11] This mechanism activates the damage recognition system, which includes toll-like receptor 4 (TLR-4) and purinoceptor type 2X7 (P2X7), resulting in the NLRP3 inflammasome activation cascade, producing severe tubulointerstitial.^[12] Numerous natural and herbal compounds, such as flavonoids and alkaloids, have positive effects on nephrotoxicity. Plants having nephroprotective characteristics are an increasingly prevalent subject in both traditional and modern medicine due to their capacity to protect the kidneys from injury in a variety of ways. These plants are resistant to the nephrotoxic effects of chemicals and medications because they contain a variety of phytochemicals, including terpenoids, polyphenols, and flavonoids.^[13] An increase in kidney problems around the world has prompted studies into natural medications that could supplement conventional forms of treatment by providing a safe choice with no adverse effects. The specific receptors and proteins that render a chemical nephrotoxic vary depending on the substance. This happens because the kidneys are actively.^[14]  Quercetin is a natural flavonoid that has antioxidant or nephroprotective properties. Reduce ROS production. Activate the Nrf2 antioxidant response element pathway. Increase the expression of antioxidant enzymes. Suppress inflammation. Prevent kidney cell death (apoptosis).^[15] The benzopyran-4-one skeleton, or chromone ring structure, has been labelled a "privileged scaffold in drug discovery." The benzopyran-4-one ring structure serves as the foundation for all flavonoid compounds. The flavonoid subclasses are formed by substituent groups at positions 2, 3, 5, 6, 7, and 8.^[16] Chromones (4H-1-Benzopyran-4-ones) are an important class of oxygen heterocyclic compounds with a benzo-γ-pyrone structure. These compounds have shown a wide range of biological properties including antibacterial, anticancer, anti-inflammatory, and antioxidative, and because to their low toxicity in animals, various medicines from this family have been produced, such as Chromonar, Flavoxate, and Scutellarein. ^[17] Acid chloride ester pharmacophores were chosen as possible inhibitors of NFKB and TNF-alpha. The design of test ligands with increased nephroprotective efficacy is inspired by the structural properties of standard drugs such as Quercetin. ^[18] This is where we present our study, in which we designed an ester derivative capable of lowering kidney toxicity and oxidative stress. The 3-hydroxy-2-phenyl-4H-1-Benzopyran-4-one (Flavonol) ester derivatives have higher lipophilicity than their hydroxyl flavone counterparts, allowing them to penetrate through the cell membrane during pharmacological tests. ^[19]

2. MATERIAL AND METHODS

1. 1. Protein preparation

Download the target protein's 3D crystal structure in PDB file format from the Protein Data Bank (RCSB, www.rcsb.org) and use the right PDB code. Based on the following parameters: ligand co-crystallized with the protein (helps pinpoint the binding site), and protein without missing parts.^[20] The formed protein structure also included water molecules and cofactors. Cofactors and water molecules appeared to be excluded from a PDB file after being loaded into the MVD Version 6.0 application. Furthermore, polarization of hydrogen, protonation states, and undefined charge assignment were done via the Molegro Virtual Docker.^[21]

1. 2. Ligand Preparation

The 2D structures of ten benzopyran ester derivates (3a-3j)  (Table 1) and a reference drug (querecetin) as ligands were obtained using ChemDraw software. The 2D structure was then transformed to a 3D structure using ChemDraw ultra, and the geometry was optimized using MM2 energy minimization in order to assure that the ligand accepts low energy. ^[22,23]

3-(susbtsituted-1,3-dien-1-yloxy)-2-phenyl-4H-chromen-4-one

Compound Id	R	Compound Id	R
3a		3f
3b		3g
3c		3h
3d		3i
3e		3j

Table 1.  List of novel design ester derivatives.

Figure 1. 2D interaction of protein-ligand complex of designed potent compounds along with standard drug against the target protein generated by the Molegro virtual docker v.6.0 software.

CONCLUSION

The present work confirmed that novel Benzopyran derivatives carrying an ester functionality could be good nephroprotective agents by using an inbuilt computational approach. Molecular docking studies proved interesting interactions occurred between the designed compound and the selected target protein and further modification of the benzopyran scaffold by incorporating an ester group could lead to better binding at the target site and molecular recognition. The interaction profiles indicated the ability of these derivatives to form stable protein-ligand complexes within the active site. Moreover, the ADMET parameters indicated good drug-like properties, favourable pharmacokinetic properties, and a safety profile for the designed molecules. The compounds were found to be compliant with drug-likeness parameters and were potentially promising for further drug development studies. In conclusion, the results suggest that ester derivatives of benzopyrans are an interesting group of compounds for the identification of novel nephroprotective drugs. The study offers a solid computational basis to drive any future synthetic application and study of the biological activity. Experimental validation of the molecules through synthesis, characterization, in vitro nephroprotective screening, mechanistic studies, and in vivo evaluation is further key to confirm their therapeutic potential and progress toward developing effective nephroprotective drugs.

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