1. INTRODUCTION:

Ilaprazole, the newer generation of benzimidazole proton pump inhibitors (PPIs), is used to treat duodenal and gastrointestinal (GI) ulcers. It is mainly metabolized by non-enzymatic degradation and partially by CYP3A4 and CYP3A5, but hardly by CYP2C19, where traditional PPIs undergo biotransformation catalyzed by CYP2C19 and CYP3A4, with CYP2C19 playing the predominant role.^1,2 .

It is commonly recognized that CYP2C19 genetic variations affect the pharmacokinetics and therapeutic effectiveness of numerous PPIs.^3,4In contrast to traditional proton pump inhibitors, ilaprazole exhibits a favourable extended half-life and low pharmacokinetic variability linked to the CYP2C19 genetic polymorphism. As a result, its disposition and therapeutic effects are not greatly impacted by this polymorphism.^4,5

CYP2C19 enzyme plays a crucial role in the metabolism of many drugs and PPIs are found to be potent inhibitors of CYP2C19, thereby affecting the clinical outcome of certain drugs that are administered concomitantly due to pharmacokinetic interaction.^6,7,8 PPIs with weaker inhibitory effects on CYP2C19 may be effective in such cases. However, more research is needed to understand the exact mechanism of ilaprazole’s interaction with CYP2C19. This study aimed to assess the CYP2C19 inhibitory potential of various PPIs through molecular docking strategy and identify the drug that has the least binding affinity towards CYP2C19. Furthermore, in-silico Absorption, distribution, metabolism, excretion (ADME), and drug-likeness properties of the molecules were also evaluated.

2. METHODOLOGY:

Selection of ligands:

The ligand molecules, Ilaprazole, Pantoprazole, Omeprazole, Esomeprazole, Lansoprazole, Dexlansoprazole, Rabeprazole, Dexrabeprazole were collected from PubChem (https://pubchem.ncbi.nlm.nih.gov/). The ligands (3D conformer) were saved in PDB format for further process.

Selection of proteins:

The 3D structures of the target proteins were retrieved from the Protein Data Bank (http://www.rcsb.org). (PDB IDs:, 4GQS, 4D7D) (Figure S1-S2) and it was downloaded in PDB format for docking procedure.

Bioactivity Score of Selected Compounds:

A molinspiration screening, which is performed to determine the bioactivity score of Ilaprazole and other traditional PPIs is a type of in silico screening that involves computational techniques to assess the chemical database to determine kinase inhibitors, protease inhibitors and enzyme inhibitors as well as ligands modulating G-Protein coupled receptor (GPCR) ion channels and nuclear receptors.

ADMET analysis and Molecular Docking:

The ligand structures were analysed for pharmacokinetic parameters (ADME), toxicity, drug-likeness, and molecular characteristics using the pkCSM online web server. The PPI ligands and the CYP450 protein (CYP2C19, CYP3A4) were molecularly docked using CB-Dock2, a protein-ligand blind docking web server built on AutoDock Vina (version 1.1.2). To estimate the inhibitory capability of several proton pump inhibitors, docking analysis was used.

3. RESULTS:

To determine the binding affinity of PPIs (ligands) over proteins (CYP3A4, CYP2C19), molecular docking has been performed. The CB-DOCK 2 tool was utilized to dock ligands over 4GQS and 4D7D.

Ilaprazole Interaction with CYP2C19

Ilaprazole Interaction with CYP3A4

Figure 1: Pictorial 3D view of Molecular Docking of Protein-ligand interactions (Binding conformation and associated intermolecular interactions of Ilaprazole with CYP2C19 and CYP3A4)

Table 1: Comparison of Vina Score of Ilaprazole with Traditional Proton Pump Inhibitors

PPIs (Ligands)	Vina Score Protein-CYP3A4 (PDB Code-4D7D)	Vina Score Protein-CYP2C19 (PDB Code-4GQS)
Ilaprazole	-7.0	-8.0
Pantoprazole	-7.5	-8.2
Omeprazole	-7.8	-8.7
Esomeprazole	-7.4	-8.7
Lansoprazole	-9.3	-9.0
Rabeprazole	-7.6	-8.1
Dexlansoprazole	-9.1	-9.1
Dexrabeprazole	-7.8	-8.1

The lower value of vina score indicates a stronger binding affinity towards the protein.

The higher value indicates lesser affinity or interaction. Ilaprazole found to have high vina score compare to other PPIs for both the proteins that docked (4GQS and 4D7D)

(a) 2D molecular docking of Ilaprazole with CYP2C19 (4GQS) (b) 2D molecular docking of Ilaprazole with CYP3A4 (4D7D)

Figure 2: Molecular docking 2D images of Ilaprazole towards protein 4GQS and 4D7D

Table 2: Comparison of Bioactivity Score of Ilaprazole with traditional Proton pump Inhibitors

PPIs	GPCR Ligand	Ion Channel Modulator	Kinase Inhibitor	Nuclear Receptor ligand	Protease Inhibitor	Enzyme Inhibitor
Ilaprazole	0.29	0.03	0.20	-0.41	-0.19	0.35
Pantoprazole	0.07	-0.23	0.06	-0.28	-0.55	0.37
Omeprazole	0.24	-0.23	0.08	-0.21	-0.23	0.43
Esomeprazole	0.24	-0.23	0.08	-0.21	-0.23	0.43
Lansoprazole	0.27	-0.13	0.13	-0.03	-0.09	0.41
Rabeprazole	0.26	-0.19	0.13	-0.14	-0.08	0.38
Dexlansoprazole	0.27	-0.13	0.13	-0.03	-0.09	0.41
Dexrabeprazole	0.26	-0.19	0.13	-0.14	-0.08	0.38

Table 3: ADMET Analysis of Ilaprazole vs Traditional Proton Pump Inhibitors

ADMET Parameters	Ilaprazole	Pantoprazole	Omeprazole and Esomeprazole	Lansoprazole and Dexlansoprazole	Rabeprazole and Dexrabeprazole
Intestinal absorption (%)	93.199	89.622	90.632	84.059	87.447
P-glycoprotein substrate	YES	YES	YES	YES	YES
P-glycoprotein I inhibitor	NO	NO	NO	YES	NO
P-glycoprotein II inhibitor	NO	NO	NO	NO	NO
VDss (human)	0.171	0.219	0.28	0.086	0.126
Fraction unbound	0.181	0.318	0.251	0.245	0.238
BBB permeability	-0.324	-0.798	-0.288	-0.01	0.067
CNS permeability	-2.533	-3.473	-2.622	-2.452	-2.806
CYP2D6 substrate	NO	NO	NO	NO	NO
CYP3A4 substrate	NO	NO	NO	NO	NO
CYP1A2 inhibitior	YES	YES	YES	YES	YES
CYP2C19 inhibitior	YES	YES	YES	YES	YES
CYP2C9 inhibitior	NO	NO	NO	NO	NO
CYP2D6 inhibitior	NO	NO	NO	YES	NO
CYP3A4 inhibitior	YES	YES	YES	YES	YES
Total Clearance	1.012	0.846	0.972	0.685	1.159
Renal OCT2 substrate	YES	YES	YES	YES	YES
AMES toxicity	YES	YES	YES	YES	YES
Max. tolerated dose (human)	0.485	0.563	0.5	0.424	0.428
hERG I inhibitor	NO	NO	NO	NO	NO
hERG II inhibitor	YES	NO	NO	NO	NO
Oral Rat Acute Toxicity (LD50)	2.184	2.184	2.201	1.781	1.715
Oral Rat Chronic Toxicity	0.544	1.833	1.906	2.009	2.103
Hepatotoxicity	YES	YES	YES	YES	YES
T.Pyriformis toxicity	0.285	0.285	0.285	0.285	0.285
Minnow toxicity Inhibitior	0.994	0.809	-0.36	0.219	0.289

4. DISCUSSION:

Drug-likeness Analysis:

Using Lipinski's rule of five, all of the chosen proton pump inhibitors were prepared for drug-likeness analysis. All of the PPIs' analyses revealed no infractions of the regulations, indicating that their absorption or permeation would function properly ^9-12.

Molecular Docking:

To assess the protein-ligand interactions for the binding affinity CB dock tool were used. The projected binding affinity between the ligand and the protein is measured by the Vina score, where a lower value denotes a stronger binding affinity and vice versa.^13-18

All compounds showed negative values of binding energy. This result suggested the favourability of their interactions with the CYP2C19 (Table 1). The binding energy of ilaprazole was found to be – 7.0 kcal/mol for 4D7D (CYP3A4) and -8.0kcal/mol for 4GQS (CYP2C19). The binding energy values for CYP2C19 were calculated for PPIs as follows: Ilaprazole> Dexrabeprazole and Rabeprazole> Pantoprazole> Omeprazole and Esomeprazole >Lansoprazole >Dexlansoprazole. Since Rabeprazole, Dexrabeprazole, and Ilaprazole were calculated with high vina score it might have less binding affinity compared to other PPIs.¹⁹ Ilaprazole was found to have the highest vinascore compared to other PPIs for the protein 4D7D which shows that it has the lowest binding affinity among other PPIs for CYP3A4 protein. The hydrogen bond interactions of ilaprazole with CYP2C19 and CYP3A4 protein has been shown in the 2D image (Figure 2)

Bioactivity Score:

Using molinspiration cheminformatics software, the bioactivity score for ilaprazole and other conventional PPIs was determined; the results are displayed in (Table 2). It is well established that substances have more biological activity if their bioactivity score is higher than zero.^20-22The compounds in this investigation were effective as kinase and enzyme inhibitors, as demonstrated by the bioactive data of PPIs. Every PPI functions as a nuclear ligand-receptor.

ADMET Prediction (Absorption, Distribution, Metabolism, Elimination and Toxicity):

The pharmacokinetics (PK) parameters like blood-brain barrier penetration, human oral bioavailability, a P-glycoprotein inhibitor, CYP2C19 inhibitor, CYP3A4 inhibitor, CYP2D6 inhibitor, CYP inhibitory promiscuity, carcinogenicity, AMES, and acute oral toxicity, it was decided to submit the ligand structures to the pkCSM software^.23 (Table 3). Based on prediction results, ilaprazole was determined to be an inhibitor of CYP2C19 and CYP3A4. It was discovered that every other conventional PPI was a CYP2C19 inhibitor.²⁴All other PPIs are proven to be CYP3A4 inhibitors, except rabeprazole.

5. CONCLUSION:

The present study concluded that ilaprazole has an inhibitory effect on CYP3A4 and CYP2C19 isoforms of CYP450. But when compared to other traditional PPIs that are widely used, ilaprazole was found to have the least inhibitory potential. Drugs that exhibit pharmacokinetic drug interaction with proton pump inhibitors mediated by these enzymes resulted in poor therapeutic outcomes. In such cases, ilaprazole might be the suitable option among PPIs. More in-vitro and in-vivo research should be carried out to validate these findings.

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Received on 21.03.2024 Revised on 12.07.2024

Accepted on 08.09.2024 Published on 27.03.2025

Available online from March 27, 2025

Research J. Pharmacy and Technology. 2025;18(3):1113-1117.

DOI: 10.52711/0974-360X.2025.00160

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