Molecular Docking/ADME-TOX-Based Analysis for New Anti-Colorectal Cancer Through Peroxiredoxin 1 Inhibition ^†

Abstract

Colorectal cancer ranks as the third most prevalent form of cancer on a global scale. The abnormal expression of Peroxiredoxin 1, or PRDX1, plays an important role in cancer progression and tumor cell survival. This makes inhibiting this protein a promising target for colorectal cancer treatment. In order to develop effective PRDX1 inhibitors, a drug design investigation based on computational methods was carried out using a collection of recently synthesized compounds derived from two main chemical base structures: C-5 sulfenylated amino uracils and 1,2,3-triazole benzothiazole derivatives. To obtain the PRDX1 protein PDB ID: 7WET, molecular docking was performed on the studied compounds in combination with PRDX1. The 1,2,3-triazole benzothiazole derivatives showed interesting docking results. For instance, nine promising candidates were distinguished by their formation of better stable complexes with PRDX1 in terms of E (binding) from −7.0 to −7.3 kcal/mol, namely, 7WET-L18, 7WET-L17, 7WET-L25, 7WET-L19, 7WET-L20, 7WET-L26, 7WET-L22, 7WET-L23, and 7WET-L24, as well as an E of −6.8 kcal/mol for Celastrol, a known PRDX1 inhibitor. Moreover, an extensive evaluation of ADME-TOX was performed to predict the pharmacokinetic, pharmacodynamic, and toxicological properties of the compounds studied. The findings offer significant support for the prospective application of these analogs in the fight against colorectal cancer.

1. Introduction

Colorectal cancer (CRC) plays a major role in the worldwide cancer burden, standing out as one of the most frequently occurring cancers across the globe [1,2]. Among the factors involved in CRC pathogenesis, initiation, and development is oxidative stress [3], which is the imbalance between reactive oxygen species (ROS) [4] and antioxidants such as Peroxiredoxins (Prxs) [5], leading to cell damage [2].

Peroxiredoxin 1 (PRX1) is a transcriptional factor expressed during early limb bud mesoderm development [6], belonging to the Prxs family. PRRX1 significantly enhances the growth, survival, and stem cell-like characteristics of CRC via the JAK2/STAT3 pathway by affecting IL-6 as a major transcriptional factor regulating its transcription in CRC [7]. Studies show that PRRX1 plays a crucial role in cell growth and has been suggested as a dependable biomarker for evaluating the probability of tumor metastasis in CRC [8]. Moreover, it was discovered that chemotherapy may exclusively improve the prospects of CRC patients with diminished PRRX1 expression. This makes PRX1 a pivotal target for advancements in anti-CRC therapies [7].

In order to develop effective PRDX1 inhibitors, a drug design investigation based on computational methods was carried out using a collection of recently synthesized compounds, derived from two main chemical base structures—thiol-linked pyrimidine derivatives [9] and 1,2,3-triazole benzothiazole derivatives [10]. To obtain the PRDX1 protein PDB ID: 7WET, molecular docking was performed on the studied compounds in combination with PRDX1.Furthermore, an extensive evaluation of ADME-TOX was performed to predict the pharmacokinetic, pharmacodynamic, and toxicological properties of the compounds studied. The findings offer significant support for the prospective application of these analogs in the fight against colorectal cancer.

2. Materials and Methods

Twenty-seven compounds belonging to thiol-linked pyrimidine and 1,2,3-triazole benzothiazole derivatives were optimized by HyperChem software [11]. The compounds were docked by Autodock Vina [12] using the PyRx—Virtual Screening Tool (https://pyrx.sourceforge.io/, accessed on 5 September 2024). ADME-T prediction of the best compounds out of those selected was conducted using some wed tool such as SwissADME (http://www.swissadme.ch/, accessed on 5 September 2024) and PKCSM (https://biosig.lab.uq.edu.au/pkcsm/, accessed on 5 September 2024).

3. Results and Discussion

3.1. Molecular Docking

A molecular docking study was conducted for twenty-seven derivatives with PRDX1 in their 7WET protein PDB structure. L18 had the best energy score compared to the other compounds (−9.4 kcal/mol). Figure 1 shows the 2D and 3D interaction diagrams between the active site of 7WET and L18.

The total score energy results of the docked complexes, alongside their distances, types of interactions, key residues, atoms involved in the compounds, and the receptor for the 7WET target, are summarized in

Table 1. Docking score and interactions between compounds and 7WET active site.

Complex	Binding Affinity (kcal/Mol)	Bonds Between the Compounds, Atoms, and Active Site Residues (Chain A)
		Interaction Type	Receptor Residues	Receptor Atoms	Compound Atoms	Distance (A°)
Ref1	−6.8	Pi-Pi stacked	Phe50	6-ring	6-ring	4.4
L18	−7.4	H-Bond H-Bond	Gly95 Gln94	O O	NH H5	2.28 2.97
L17	−7.3	H-Bond H-Bond	Gly95 Thr49	O O	NH NH	2.28 2.59
L25	−7.3	H-Bond H-Bond	Gly95 Thr49	O O	NH NH	2.22 2.65
L19	−7.2	H-Bond H-Bond	Gly95 Gly94	O O	NH C	2.19 3.5
L20	−7.2	H-Bond	Gly95	O	NH	2.1
L26	−7.2	H-Bond	Gly95	O	NH	2.07
L22	−7.0	H-Bond	Gly95	O	NH	2.13
L23	−7.0	H-Bond	Gly95	O	NH	2.24
L24	−7.0	H-Bond	Gly95	O	NH	2.18

.

The reference molecule had a score energy of −6.8 Kcal/mol, without the formation of H-Bonds; however, it showed Pi-Pi interactions with the PHE50 residue.

The nine best compounds were ordered according to their affinity for the formation of stable complexes with the 7WET protein as follows: 7WET-L18 < 7WET-L17, 7WET-L25 < 7WET-L19, 7WET-L20, 7WET-L26 < 7WET-L22, 7WET-L23, and 7WET-L24. Their energy scores were −7.4, −7.3, and −7.2 (kcal/mol), respectively.

3.2. Evaluation ADME-TOX

ADME-T properties play a significant role in drug development [13].

Table 2. ADME-T properties of candidate compounds.

Category	Model Name	L25	L20	L26
Absorption	Water solubility	−5.57	−4.91	−5.57
	Caco-2 permeability	0.75	0.98	0.75
	HIA (%absorbed)	83.3	90.3	83.6
	P-gp substrate	Yes	Yes	Yes
	P-gp I inhibitor	Yes	Yes	Yes
Distribution	VDss	−0.25	−0.34	−0.28
	BBB permeability	−2.01	−1.39	−1.99
Metabolism	CYP2D6 substrate	No	No	No
	CYP3A4 substrate	Yes	Yes	Yes
	CYP1A2 inhibitor	No	No	No
	CYP2C19 inhibitor	Yes	Yes	Yes
	CYP2C9 inhibitor	Yes	Yes	Yes
	CYP2D6 inhibitor	No	No	No
	CYP3A4 inhibitor	Yes	Yes	Yes
Excretion	Total clearance	0.76	0.73	0.78
	T1/2 (h)	1.14	0.72	1.06
Toxicity	AMES toxicity	No	No	No
	Maximum tolerated dose (log mg/kg/day)	0.69	0.68	0.69
	HERG I inhibitor	No	No	No
	HERG II inhibitor	Yes	Yes	Yes
	Oral rat acute toxicity (LD50) (mol/kg)	2.41	1.75	2.41
	Hepatotoxicity	No	No	No
	Skin sensitization	No	No	No

summarizes the best pharmacological property profiles of ligands 25, 20, and 26. According to the presented results, all selected compounds had high human intestinal absorption, and they were P-gp substrates. It is worth nothing that all these compounds could not pass through the BBB. These molecules had a similar metabolic profile; they were all metabolized by CYP3A4. The total clearance (CLtot) value of the molecules ranged from 0.73 to 0.78 mL/min/kg, with a T1/2 (h) value between 0.7 and 1.14. No compound presented AMES toxicity, hepatotoxicity, nor skin sensitization. The LD50 value of the studied molecules ranged from 1.75 to 2.4 mol/kg.

4. Conclusions

According to these findings, we revealed that the three selected cytotoxic molecules—L25, L20, and L26—had very important structures, without toxicity. As such, they should be pay attention to in future studies in order to improve their properties and employ them as effective PRDX1 inhibitors against colorectal cancer.