Design and In Silico Study of 3,5-Dinitrocatechol and Its Derivatives for Antiparkinsonian Activity

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder marked by dopamine deficiency in the brain. Catechol-O-methyltransferase (COMT) is an enzyme responsible for the degradation of dopamine, and its inhibition can prolong dopamine activity. The current study focuses on designing and evaluating derivatives of 3,5-dinitrocatechol (DNC) through in silico methods for potential COMT inhibition. The crystal structure of the COMT enzyme (PDB: 4XUC) was used as the receptor for molecular docking studies. Entacapone, a standard COMT inhibitor, was used as a reference drug. Six derivatives of DNC were designed and analyzed using PyRx for docking, SwissADME for pharmacokinetic analysis, and ProTox-II for toxicity prediction. Among the derivatives, D6 showed the highest binding affinity (-6.6 kcal/mol) compared to Entacapone (-5.5 kcal/mol), with good ADME properties and minimal toxicity. The results indicate D6 as a promising COMT inhibitor candidate for Parkinson’s therapy.

Keywords

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that impairs motor function due to the depletion of dopamine in the brain. Among the enzymes involved in dopamine metabolism, Catechol-O-Methyltransferase (COMT) plays a significant role by methylating catecholamines such as dopamine, thereby decreasing their availability. The inhibition of COMT has emerged as an effective therapeutic strategy to prolong dopamine activity in PD patients. Currently available COMT inhibitors like Entacapone exhibit limited CNS penetration, which compromises their therapeutic efficacy. Therefore, the development of novel COMT inhibitors with better pharmacokinetic and pharmacodynamic profiles is of great interest. Recent advancements in computer-aided drug design (CADD) have enabled the use of in silico approaches such as molecular docking, ADMET prediction, and toxicity screening to identify promising drug candidates. The present study aims to design, screen, and evaluate derivatives of 3,5-dinitrocatechol (DNC), a known COMT-inhibiting scaffold, for their potential to serve as effective and safer alternatives to existing COMT inhibitors, using structure-based virtual screening methodologies involving the crystal structure of human COMT (PDB ID: 4XUC).

2. MATERIALS AND METHODS

Software Tools Used:

• ChemSketch: Used to draw 2D structures, generate SMILES, and IUPAC names.
• Avogadro: For geometry optimization and conversion to 3D formats.
• PyRx: For molecular docking and virtual screening.
• Discovery Studio Visualizer: For docking result analysis.
• SwissADME & pkCSM: For physicochemical and ADME property predictions.
• ProTox-II: For toxicity analysis.

Ligand Preparation: The ligands (DNC and its derivatives) were drawn using ChemSketch, optimized using Avogadro, and converted into PDB format. SMILES notations were generated and used for ADME and toxicity studies.

Fig no.1 Structure of Ligand

Receptor Preparation: The COMT enzyme (PDB ID: 4XUC) was retrieved from the RCSB Protein Data Bank. Preprocessing involved removal of water molecules, heteroatoms, and charge stabilization using AutoDock tools within PyRx.

Fig no.2- Structure of receptor 4xuc

Docking Methodology: The docking was performed using PyRx (Vina Wizard). All ligands were converted to PDBQT format. Binding affinities were recorded and interactions analyzed using Discovery Studio Visualizer.

Fig no.3-Receptor (4xuc)- Ligand (standard drug- Entacapone) visualisation

Fig no.4-Receptor (4xuc)- Ligand(D6) visualisation

Interpretation:

Name	Structure	IUPAC Name	Smile Notation	Binding Affinity
Entacapone		(2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide	[O][N+](=O)c1cc(cc(O)c1O)\C=C(/C#N)C(=O)N(CC)CC	-5.5

Ligand and it’s derivatives:

Sr No.	Structure	IUPAC Name	Smile Notation	Binding Affinity
D1		3,5-dinitrobenzene-1,2-diol	Oc1cc(cc([N+](=O)[O])c1O)[N+](=O)[O-]	-5.0
D2		3,4-dihydroxy-5-nitrobenzaldehyde	O=Cc1cc(O)c(O)c(c1)[N+](=O)[O-]	-5.1
D3		3,4-dihydroxy-5-nitrobenzoyl fluoride	FC(=O)c1cc(O)c(O)c(c1)[N+](=O)[O-]	-5.0
D4		(3,4-dihydroxy-5-nitrophenyl)(2-hydroxyphenyl)methanone	O=[N+]([O-])c1cc(cc(O)c1O)C(=O)c1ccccc1O	-6.0
D5		(3,4-dihydroxy-5-nitrophenyl)(3-fluoro-2-hydroxyphenyl)methanone	O=[N+]([O])c1cc(cc(O)c1O)C(=O)c1cccc(F)c1O	-6.0
D6		(3,4-dihydroxy-5-nitrophenyl)[3-(fluoromethyl)-2-hydroxyphenyl]methanone	O=[N+]([O-])c1cc(cc(O)c1O)C(=O)c1cccc(CF)c1O	-6.6

1)Standard drug Entacapone

Entacapone is highly absorbable, does not cross the BBB, and has minimal CYP-mediated interactions, making it a reliable peripheral COMT inhibitor.

The toxicity profile shows that Entacapone has potential respiratory toxicity (active, 0.89), mutagenicity (active, 0.65), and stress response activation (Nrf2/ARE & HSE pathways active, 0.92)

High GI Absorption → Good oral bioavailability.

D6 has a better toxicity profile,than entacapone with nutritional toxicity & immunotoxicity. This makes it a potentially safer candidate with only mild risks.

6. CONCLUSION

The D6 derivative of 3,5-dinitrocatechol shows strong potential as a COMT inhibitor for Parkinson’s disease, with a better binding affinity (-6.6 kcal/mol) compared to Entacapone. Its pharmacokinetic profile is promising, with high GI absorption. Additionally, it exhibits minimal CYP enzyme inhibition, reducing the risk of drug-drug interactions. Toxicity analysis suggests D6 is generally safe, with no neurotoxicity, carcinogenicity, or BBB barrier concerns, though mild risks exist for nutitional & immunotoxicity.

Overall, D6 is a strong candidate for further development as a Parkinson’s therapy, offering improved efficacy and a favorable safety profile.

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