Evaluation of 3-Ethyl-5-fluoro-2-phenylimino-thiazolidin-4-one derivatives: Molecular docking against kinase protein and ADME studies

 

Shreyash D. Kadam¹, Denni Mammen¹*, Laxmikant B. Nikam², Rahul R. Bagul², Ajit Borhade²

¹School of Science, Navrachana University, Vasana-Bhayli Road, Bhayli, Vadodara, Gujarat, India, 391410.

² Gujarat Fluorochemicals Limited, Ranjitnagar, Panchamahal, Gujarat-389380, India.

 

ABSTRACT:

A number of new compounds have been synthesized by the authors containing fluorinated thiazolidin-4-one ring. With the aim to assess the anti-cancer potential of all the synthesized derivatives,theywere computationally tested against 1T46 C-Kit Tyrosine Kinase protein. Almost all of the evaluated derivatives showed decent affinity towards the protein, with favourable binding poses through hydrogen bonding, halogen binding and pi-sigma bonding. The amino acid lysine at position 623 in the protein chain exhibited hydrogen bond formation with each compound, along with other amino acids. Furthermore, the in silico ADME predictions suggest that the majority of the synthesized compounds exhibit favourable drug-like characteristics, with low potential for adverse effects and toxicity. The molecules possessing oxygen-containing functionalities such as –NO₂, -OCF₃, -OCF₂CF₂H and –OH have been shown to be able to cross the Human Intestinal lining. The fluorine-containing moieties such as difluoro, trifluoro, -CF₃, chloro-fluoro, and difluorobenzylamino were predicted in order to cross BBB (Blood-Brain-Barrier). Current study has revealed that the synthesized compounds show promising anticancer potential.

 

 

 

INTRODUCTION: 

In the current era, various diseases are emerging day by day and their treatment is a challenging issue for the world. Past few years have witnessed significant advancement in computational technology which provided one of the best gift to scientific researchers specially in the field of medicinal chemistry which contributed a lot to drug discovery and given rise to many new possibilities i.e. the ability to accurately predict the biological activity of compounds to stimulate new possibilities for the advancement of novel drugs design.

 

The major advantages of in-silico study is that it is fast, reliable, productive, cost-effective, also it saves actual resources i.e. just conducting an in-vitro study randomly which end up getting poor results, moreover docking

 

which is a sub-category of in-silico study helps us to predict exact binding sites and select exact target protein by which we can determine precise biological activity. In short, docking and ADME^1–3 studies assist in study molecular biology based on structure, and drug design using computational tools. Docking analysis^4–7 is an eye-catching technique used to identify drug-biomolecule interactions for the rational drug design⁸ and themain objective of analysing the docking between ligand and protein is to predict the accurate binding modes of a ligand with the 3D protein structure from structure databases such as Protein Data Bank (PDB). There are various types of molecular docking interactions⁹ such as drug-protein or ligand-protein, protein-protein, protein-nucleic acid, enzyme-substrate, and drug-nucleic acid interactions. Thus we can define molecular docking technique as a computational technique which includes a proper protocol by which we can predict the conformation or binding sites of a receptor-ligand complex, where the receptor is usually a protein molecule and the ligand is a synthesized small molecule. If everything works perfectly then it results in formation of stable protein-ligand adduct¹⁰that are vital to execute their biological functions and depending upon selected target and ligand binding properties, it predicts the three-dimensional structure of complex and provides binding affinity¹¹.

 

The drug preparation also involves evaluation of absorption, distribution, metabolism and excretion i.e. ADME^12–17 properties and at the preliminary stages of drug discovery if these properties are known so it decreases chances of failures in pharmacokinetics properties in later phases of development due to which drug moiety will reach the market more efficiently. Moreover, for a synthesized compound to function as an effective drug, it must not only reach its target within the body at the appropriate concentration but also remain in that location in a bioactive state for a sufficient duration to facilitate the intended biological processes. Therefore in this study, we have also made use of the Swiss ADME web tool^1–3 for analyzing pharmacokinetics, physicochemical properties, drug-likeness and medicinal-chemistry friendliness, in addition to which we obtained unique boiled egg diagram which was helpful for understanding HIA and BBB pattern on scale of WLOGP vs TPSA. Hence, by using this computational method we can perform virtual screening and select the most interesting and promising molecules from the synthesized moieties and proceed them for their further modifications or for in-vitro studies.

 

Thiazolidinone^18–26 also known as “wonder nucleus”²⁷ are the oxo derivatives of thiazolidine group that is pertaining to a significant class of heterocyclic compounds characterized by the presence of sulfur and nitrogen atoms, along with the carbonyl group situated at the fourth position within a five-membered ring. ^28–34. Also importance of fluorine³⁵ is well known and it was observed that small organic molecules which act as pharmaceutical drugs mostly consist of at least one fluorine atom or a fluorinated functional group like CF3, Ar-F in its structure. It was reported in many papers that around 20% of the marketed drugs were fluorinated organic compounds. Numerous of these compounds have fluorinated aniline as a precursor for its synthesis.

 

In the present work we have undergone in silico analysis³⁶ of novel 3-Ethyl-5-fluoro-2-phenylimino-thiazolidin-4-one (2-19) derivatives which were synthesized using different Fluorinated anilines against 1T46 target protein Figure. 1^37–39. In addition to this, we also have selected doxorubicin Figure 1 as standard due to the fact that further we are going to continue this study for in-vitro anticancer^40,41 evaluation in which we are going to take doxorubicin as our standard⁴². So in order to gain full details of the drug we had performed docking and ADME analysis for doxorubicin⁴⁰as well.

 

Shown below Figure 1 are the synthesized derivatives on which in silico studies have been performed against kinase protein 1T46.

 

Figure 1. C-Kit tyrosine kinase Protein ⁴³ 1T46 used as targeting macromolecule for molecular docking, doxorubicin (1) anti-cancer standard and synthesized novel fluorinated thiazolidin-4-one derivatives(2-19).

 

MATERIALS AND METHODS:

In silico activity:

1) Docking Study:

In this research, we assessed the affinity and binding modes of the studied molecules with respect to the target protein ^38,39. Initially, the crystal structures of the target proteins (see Figure 1) had their water molecules removed, leaving behind only the main-chain amino acids crucial for binding. The co-crystallized ligands served as reference points for identifying the binding pockets, after which they were removed. Subsequently, polar hydrogen atoms were added to the protein structures for protonation. The structures of the investigated compounds (Figure 1) were drawn using ChemDraw Ultra 7.0 and BIOVIA Discovery Studio Visualizer 2021, and these structures were saved in PDB format. Subsequently, the saved files were imported into MGL AutoDock Tools software for protein preparation. The protein was selected as the macromolecule and then saved in PDBQT format. A configuration file was generated, containing information such as the receptor name, ligand name, output file name, and the X, Y, Z coordinates of the grid box, along with the size dimensions of the grid box (X, Y, Z). The ligand was prepared, and any available rotatable bonds were added. The next step involved the use of the Command Prompt to execute the AutoDock Vina software for each target receptor by ligand, by entering the necessary codes or commands. In each case, the algorithm generated 9 docked structural poses, along with data on affinity and RMSD. Out of which one best pose was selected and its interactions were shown in Figures 2 and 3 and Tables 1, 2 and 3.

 

2) ADME Study:

ADME analysis was performed via using Swiss ADME site ^38,39. Chem Draw Ultra 7.0 software was employed to create the structures of the compounds. These structures were then converted into SMILES notation using the Swiss ADME tool, which also provided estimations of various physicochemical parameters and pharmacokinetic characteristics. Additionally, the BOILED EGG method was employed to predict the lipophilic nature and polarity characteristics of the small molecules has been shown in Figure 4.

 

RESULTSAND DISCUSSION:

In-silico activity:

1) Docking studies:

Docking studies^38,39 lend a hand in analysing and getting the information regarding the appropriate orientation of synthesized organic ligand within the active site also known as “pocket site” of the large molecule i.e. protein. Here the binding pockets were selected on the foundation of pre-attached inhibitor inside the crystal structure of respective proteins. The promising compound was selected on the basis of some guidelines such as docking energy at 0.00 RMSD value, binding modes and molecular interactions at the active site of the macromolecule. The synthesized ligands have been docked against C-KIT Tyrosine Kinase protein as depicted in Figure 1. The resulting docking scores and their interactions with amino acids are depicted in the Table 1.

 

The results show that substituted fluorinated thiazolidin-4-one derivatives (2-19) exhibit diverse bonding interactions like H-bonding, Pi-Sigma, and halogen interactions towards 1T46Kinase. The compounds displayeddecentaffinity values shown within the range of -7.7 to -9.2 kcal/mol with favorable binding poses. The amino acid LYS623 from kinase displayed hydrogen bonding with almost all the compounds such as 3, 4, 5, 6, 7, 8, 10, 11, 12, 14, 15, 17, 18 and 19. Apart from lysine various amino acids such as ASP810, GLY812, CYS673, THR670, HIS790, and GLY676 were also involved in H bonding with most compounds. Among 18 ligands themoiety13demonstrated strong interactions towards kinase protein, with active site amino acids with best binding energy -8.8 kcal/mol, while the molecule 19 similarly showed a valueof -9.2 kcal/mol.

 

Table 1. Docking scores and molecular interactions of the molecules with C-KIT Tyrosine Kinase protein

Compounds No.	Docking Energy	RMS	No of Interactions	Interaction Residues			No of H Bonds	Bond Length (Å)
				Pi-Sigma	Halogen	H-Bonding
Doxorubicin	-7.7	0.00	9	VAL643	-	ASP810	2	2.62003
						GLY812		2.95235
2	-7.7	0.00	5	THR670, UNK0	-	-	0	-
3	-8.2	0.00	8	VAL603, LEU799	GLU640, GLU671	LYS623	1	2.97711
4	-8.2	0.00	10	THR670, UNK0	ALA621, GLU640	LYS623	1	2.65556
5	-8.3	0.00	9	THR670, UNK0	GLU640	LYS623	1	2.81076
6	-8.5	0.00	9	THR670, UNK0	-	ASP810	2	2.3832
						LYS623		3.35007
7	-8.5	0.00	11	THR670, UNK0	ALA621, GLU640	LYS623	2	2.62329
						ASP810		2.64758
8	-8.6	0.00	12	THR670, UNK0	GLU640	LYS623	1	2.77714
9	-7.8	0.00	6	THR670, UNK0	-	-	0	-
10	-8.5	0.00	7	LEU595, LEU799, UNK0	VAL668	LYS623	1	2.89271
11	-8.5	0.00	8	LEU595, LEU799, LEU799	VAL668, GLU671	LYS623	1	2.85801
12	-7.9	0.00	14	THR670, UNK0	ALA621, VAL668	LYS623	2	2.51838
						THR670		1.55935
13	-8.8	0.00	12	THR670, UNK0	GLU640	CYS673	2	2.86699
						ASP810		2.44389
14	-8.5	0.00	12	UNK0	GLU640, ASP810	LYS623	3	2.54003
						LYS623		2.62268
						LYS623		3.05381
15	-7.8	0.00	23	LEU644	GLU640, GLU640, ILE808, CYS809, ASP810	LYS623	5	2.83288
						ASP810		2.3607
						ASP810		2.38726
						HIS790		3.31246
						UNK0		3.40309
16	-8.3	0.00	10	THR670, UNK1	-	-	-	-
17	-7.7	0.00	7	LEU799	GLU640	LYS623	2	2.82539
						GLY676		3.6142
18	-8.0	0.00	7	THR670, UNK0	-	LYS623	1	2.76003
19	-9.2	0.00	20	UNK0	GLU640, VAL668	LYS623	3	2.7977
						LYS623		2.86177
						CYS673		2.65578

 

Table 2. Total number of favorable interactions: 13

Sr No.	Name	Colour	Distance	Category	Types Of Bonds	Bond From	Bonds	Bond To	Bonds
1	A:LYS623:HZ3 - :UNK0:O11		2.7977	Hydrogen Bond	Conventional Hydrogen Bond	A: LYS623: HZ3	H-Donor	: UNK0: O11	H-Acceptor
2	A:LYS623:HZ3 - :UNK0:F22		2.86177	Hydrogen Bond; Halogen	Conventional Hydrogen Bond; Halogen(Fluorine)	A:LYS623: HZ3	H-Donor; Halogen Acceptor	:UNK0:F22	H-Acceptor; Halogen
3	A:CYS673:HN - :UNK0:S10		2.65578	Hydrogen Bond	Conventional Hydrogen Bond	A:CYS673:HN	H-Donor	:UNK0:S10	H-Acceptor
4	A:GLU640:OE2 - : UNK0:F22		3.1512	Halogen	Halogen (Fluorine)	A:GLU640: OE2	Halogen Acceptor	:UNK0:F22	Halogen
5	A:VAL668:O - :UNK0:F20		3.44341	Halogen	Halogen (Fluorine)	A:VAL668:O	Halogen Acceptor	:UNK0:F20	Halogen
6	:UNK0:C16 - A:PHE811		3.46679	Hydrophobic	Pi-Sigma	:UNK0:C16	C-H	A:PHE811	Pi-Orbitals
7	:UNK0:C16 - :UNK0		3.61395	Hydrophobic	Pi-Sigma	:UNK0:C16	C-H	:UNK0	Pi-Orbitals
8	:UNK0:C19 - A:LYS623		4.01386	Hydrophobic	Alkyl	:UNK0:C19	Alkyl	A:LYS623	Alkyl
9	:UNK0:C19 - A:LEU644		5.34396	Hydrophobic	Alkyl	:UNK0:C19	Alkyl	A:LEU644	Alkyl
10	:UNK0:C19 - A:VAL668		4.00351	Hydrophobic	Alkyl	:UNK0:C19	Alkyl	A:VAL668	Alkyl
11	:UNK0 - A:VAL603		4.87354	Hydrophobic	Pi-Alkyl	:UNK0	Pi-Orbitals	A:VAL603	Alkyl
12	:UNK0 - A:ALA621		4.72358	Hydrophobic	Pi-Alkyl	:UNK0	Pi-Orbitals	A:ALA621	Alkyl
13	:UNK0 - A:VAL654		4.83263	Hydrophobic	Pi-Alkyl	:UNK0	Pi-Orbitals	A:VAL654	Alkyl

 

Figure 2. The 2D and 3D representation of molecular docking interactions for 3-Ethyl-5-fluoro-2-(4-trifluoromethoxy-phenylimino)-thiazolidin-4-one19, against 1T46

The two best moieties observed in this docking study having the lowest affinity value are displayed below in which 3-Ethyl-5-fluoro-2-(4-trifluoromethoxy-phenylimino)-thiazolidin-4-one 19 and 3-Ethyl-5-fluoro-2-(3-trifluoromethyl-phenylimino)-thiazolidin-4-one 13 as a ligand performed molecular docking against Tyrosine Kinase 1T46. Both these molecules showed best and most favourable interactions among all synthesized molecules due to the trifluoro functionalities. Other molecules with different functionalities showed differing interactions with values just slightly lower than these two molecules. Nine different poses were observed during the docking process, and the pose with the least affinity was chosen as the most favourable docking pose. This selected pose was then used to investigate ligand interactions. The interactions were visualized using both 2D diagrams and 3D representations.

 

3-Ethyl-5-fluoro-2-(4-trifluoromethoxy-phenylimino)-thiazolidin-4-one 19 docking analysis outputs against 1T46 kinase macromolecule

Within the specific molecule, a total of 13 favourable interactions were observed as the ligand binds to the specific sites in the selected pose. Table 2 provides details about the bonds between the ligand and amino acids, including information such as origin, type, and length of the bonds.The ligand showed three types of interactions with the amino acids at specific positions in the protein chain. These include hydrogen bonds, halogen bonds and hydrophobic interaction.

 

 

3-Ethyl-5-fluoro-2-(3-trifluoromethyl-phenylimino)-thiazolidin-4-one(13) docking analysis outputs against 1T46 kinase macromolecule

Table 3: Total number of favorable interactions: 12

Sr No.	Name	Color	Distance	Category	Types of Bonds	From	Bonds	To	Bonds
1	A:CYS673:HN -:UNK0:S10		2.86699	Hydrogen Bond	Conventional Hydrogen Bond	A:CYS673:HN	H-Donor	:UNK0:S10	H-Acceptor
2	A:ASP810:HN - :UNK0:F19		2.44389	Hydrogen Bond; Halogen	Conventional Hydrogen Bond; Halogen (Fluorine)	A:ASP810:HN	H-Donor; Halogen Acceptor	:UNK0:F19	H-Acceptor; Halogen
3	A:GLU640:OE1 -:UNK0:F21		2.85466	Halogen	Halogen (Fluorine)	A:GLU640:OE1	Halogen Acceptor	:UNK0:F21	Halogen
4	A:THR670:CG2 -:UNK0		3.84625	Hydrophobic	Pi-Sigma	A:THR670:CG2	C-H	:UNK0	Pi-Orbitals
5	:UNK0:C15 - A:PHE811		3.50772	Hydrophobic	Pi-Sigma	:UNK0: C15	C-H	A:PHE811	Pi-Orbitals
6	:UNK0:C15 - :UNK0		3.77157	Hydrophobic	Pi-Sigma	:UNK0: C15	C-H	:UNK0	Pi-Orbitals
7	:UNK0:C18 - A:LEU644		4.88556	Hydrophobic	Alkyl	:UNK0: C18	Alkyl	A:LEU644	Alkyl
8	:UNK0:C18 - A:VAL654		4.2237	Hydrophobic	Alkyl	:UNK0: C18	Alkyl	A:VAL654	Alkyl
9	:UNK0 - A:VAL603		4.73897	Hydrophobic	Pi-Alkyl	:UNK0	Pi-Orbitals	A:VAL603	Alkyl
10	:UNK0 - A:ALA621		4.68568	Hydrophobic	Pi-Alkyl	:UNK0	Pi-Orbitals	A:ALA621	Alkyl
11	:UNK0 - A:LYS623		5.1237	Hydrophobic	Pi-Alkyl	:UNK0	Pi-Orbitals	A:LYS623	Alkyl
12	:UNK0 - A:VAL654		5.18833	Hydrophobic	Pi-Alkyl	:UNK0	Pi-Orbitals	A:VAL654	Alkyl

 

Figure 3. The 2D and 3D representation of molecular docking interactions for 3-Ethyl-5-fluoro-2-(3-trifluoromethyl-phenylimino)-thiazolidin-4-one(13), against 1T46

In the specific molecule, a total of 12 favorable interactions were identified as the ligand bound to the designated pocket site in the chosen pose. The ligand showed hydrogen bonds, halogen bonds and hydrophobic interaction with the protein.

 

2) ADME Study:

From the results of ADME analysis^38,39 we got to know about various properties of all 18 synthesized fluorinated structures of thiazolidine-4-ones. Basically, molecules within the white portion of the boiled egg diagram Figure 4 are having capability of being absorbed through the intestine i.e. HIA. The molecules depicted in the yellow portion are the ones which have the capability to cross the blood brain barrier i.e. BBB. During the analysis it was observed that the standard anticancer drug doxorubicin was out of the scanning range of the ADME analysis. So, it was positioned in neither yellow nor white portion of the diagram. This is because doxorubicin has low bioavailability when ingested orally due to which it is administered in form of an injectable.

 

Figure 4. ADME boiled egg diagram for the synthesized molecules

 

According to the analysis, we concluded thata total 16fluorinated moietiesi.e. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18 and 19 show promise of being able to cross the lining of human intestine. Interestingly among these 18moieties just molecule 16 which is having nitro functionalitywas not able to enter blood brain barrier and molecule 18 was on the border line andexhibits the potential of the ideal molecule that could cross the BBB barrier due to the existence of hydroxyl functionality rest all other 14molecules displayed good permeability, and capable of crossing the BBB barrier.

 

The white portion of the boiled egg diagram shows the physico-chemical space where molecules have the greatest probability of being absorbed by the human intestine. The lining of the intestines is made up of epithelial cells, which are tightly packed and covered by mucus. These cells facilitate the uptake of water and other polar substances. The derivatives containing oxygen-containing polar groups such as –NO₂, -OH, -OCF₃ and -OCF₂CF₂H are observed to be able to cross this membrane as predicted by the diagram. The yellow portion in the diagram indicated the similar space where molecules having the highest probability to cross the BBB have been predicted. This layer is made up of endothelial cells which are tightly bound to allow selective permeation of molecule to the brain cells from the bloodstream. The derivatives having relatively less polar functional groups seem to facilitate the crossing of the barrier due to the presence of lipids in the membrane. It has been observed that hydrophobic drugs cross the BBBbarrier more easily than hydrophilic drugs.

 

The derivatives having mono –CF₃, difluoro, trifluoro, amino, benzyl amino, chloro-fluoro and difluoro benzyl amino groups seem to show this property. The presences of fluorine-containing functional groups seem to increase the lipophilic character of the molecule as observed in the figure.

 

Table 3. Physico-chemical Properties

Molecule No	Physico-chemical Properties
	Formula	Molecular Weight (MW)	Number of H-bond acceptors	Number of H-bond donors	Molar Refractivity	Topological Surface Area (TPSA)
Molecule 1	C27H29NO11	543.52	12	6	132.66	206.07
Molecule 2	C11H11FN2OS	238.28	3	0	67.42	57.97
Molecule 3	C11H9F3N2OS	274.26	5	0	67.33	57.97
Molecule 4	C11H9F3N2OS	274.26	5	0	67.33	57.97
Molecule 5	C11H9F3N2OS	274.26	5	0	67.33	57.97
Molecule 6	C11H9F3N2OS	274.26	5	0	67.33	57.97
Molecule 7	C11H8F4N2OS	292.25	6	0	67.29	57.97
Molecule 8	C11H9ClF2N2OS	290.72	4	0	72.39	57.97
Molecule 9	C11H10BrFN2OS	317.18	3	0	75.12	57.97
Molecule 10	C12H13FN2OS	252.31	3	0	71.67	57.97
Molecule 11	C12H11F3N2OS	288.29	5	0	71.58	57.97
Molecule 12	C12H10F4N2OS	306.28	6	0	72.42	57.97
Molecule 13	C12H10F4N2OS	306.28	6	0	72.42	57.97
Molecule 14	C12H10F4N2OS	306.28	6	0	72.42	57.97
Molecule 15	C13H9F7N2OS	374.28	9	0	77.42	57.97
Molecule 16	C11H10FN3O3S	283.28	5	0	76.24	103.79
Molecule 17	C13H9Cl2F5N2O2S	423.19	8	0	88.98	67.2
Molecule 18	C11H11FN2O2S	254.28	4	1	69.44	78.2
Molecule 19	C12H10F4N2O2S	322.28	7	0	74.1	67.2

 

Table 4. Lipophilic nature

Molecule No	Lipophilic nature
	iLOGP	XLOGP3	WLOGP	MLOGP	Silicos-IT Log P	Consensus Log P
Molecule 1	2.58	1.27	-0.32	-2.1	1.17	0.52
Molecule 2	2.32	2.93	2.6	1.63	2.6	2.42
Molecule 3	2.44	3.14	3.72	2.44	3.44	3.04
Molecule 4	2.38	3.14	3.72	2.44	3.44	3.02
Molecule 5	2.32	3.14	3.72	2.44	3.44	3.01
Molecule 6	2.44	3.14	3.72	2.44	3.44	3.04
Molecule 7	2.32	3.24	4.28	2.84	3.88	3.31
Molecule 8	2.59	3.66	3.82	2.58	3.66	3.26
Molecule 9	2.55	3.63	3.37	2.31	3.27	3.03
Molecule 10	2.24	2.87	2.32	1.64	2.95	2.4
Molecule 11	2.46	3.07	3.44	2.44	3.8	3.04
Molecule 12	2.4	3.82	4.78	2.57	3.65	3.44
Molecule 13	2.55	3.82	4.78	2.57	3.65	3.47
Molecule 14	2.59	3.82	4.78	2.57	3.65	3.48
Molecule 15	2.89	4.7	6.95	3.47	4.76	4.55
Molecule 16	1.97	2.76	2.51	0.61	0.45	1.66
Molecule 17	3.05	5.78	6.83	3.12	5.05	4.77
Molecule 18	2.03	2.58	2.31	1.05	2.12	2.02
Molecule 19	2.72	4.12	4.76	1.72	3.21	3.31

 

Table 5. Solubility in water

Molecule	Solubility in water
	ESOL Log S	ESOL Solubility (mg/mL)	ESOL Solubility (mol/L)	ESOL Class	Ali Log S	Solubility (mg/mL)
Molecule 1	-3.91	6.72E-02	1.24E-04	Soluble	-5.2	3.46E-03
Molecule 2	-3.31	1.17E-01	4.91E-04	Soluble	-3.81	3.70E-02
Molecule 3	-3.63	6.38E-02	2.33E-04	Soluble	-4.03	2.58E-02
Molecule 4	-3.63	6.38E-02	2.33E-04	Soluble	-4.03	2.58E-02
Molecule 5	-3.63	6.38E-02	2.33E-04	Soluble	-4.03	2.58E-02
Molecule 6	-3.63	6.38E-02	2.33E-04	Soluble	-4.03	2.58E-02
Molecule 7	-3.79	4.69E-02	1.60E-04	Soluble	-4.13	2.16E-02
Molecule 8	-4.06	2.52E-02	8.65E-05	Moderately soluble	-4.57	7.89E-03
Molecule 9	-4.22	1.90E-02	5.99E-05	Moderately soluble	-4.54	9.24E-03
Molecule 10	-3.28	1.34E-01	5.30E-04	Soluble	-3.75	4.52E-02
Molecule 11	-3.6	7.29E-02	2.53E-04	Soluble	-3.95	3.20E-02
Molecule 12	-4.17	2.07E-02	6.77E-05	Moderately soluble	-4.73	5.67E-03
Molecule 13	-4.17	2.07E-02	6.77E-05	Moderately soluble	-4.73	5.67E-03
Molecule 14	-4.17	2.07E-02	6.77E-05	Moderately soluble	-4.73	5.67E-03
Molecule 15	-5.04	3.39E-03	9.07E-06	Moderately soluble	-5.65	8.46E-04
Molecule 16	-3.37	1.21E-01	4.26E-04	Soluble	-4.59	7.20E-03
Molecule 17	-5.95	4.72E-04	1.11E-06	Moderately soluble	-6.96	4.64E-05
Molecule 18	-3.17	1.71E-01	6.74E-04	Soluble	-3.87	3.42E-02
Molecule 19	-4.38	1.34E-02	4.16E-05	Moderately soluble	-5.24	1.86E-03

 

Table 5. Cont…….

Molecule	Solubility in water
	Solubility (mol/L)	Class	Silicos-IT LogSw	Silicos-IT Solubility (mg/mL)	Silicos-IT Solubility (mol/L)	Silicos-IT class
Molecule 1	6.36E-06	Moderately soluble	-3.46	1.87E-01	3.44E-04	Soluble
Molecule 2	1.55E-04	Soluble	-3.44	8.57E-02	3.60E-04	Soluble
Molecule 3	9.40E-05	Moderately soluble	-4	2.77E-02	1.01E-04	Soluble
Molecule 4	9.40E-05	Moderately soluble	-4	2.77E-02	1.01E-04	Soluble
Molecule 5	9.40E-05	Moderately soluble	-4	2.77E-02	1.01E-04	Soluble
Molecule 6	9.40E-05	Moderately soluble	-4	2.77E-02	1.01E-04	Soluble
Molecule 7	7.40E-05	Moderately soluble	-4.27	1.58E-02	5.40E-05	Moderately soluble
Molecule 8	2.71E-05	Moderately soluble	-4.33	1.37E-02	4.72E-05	Moderately soluble
Molecule 9	2.91E-05	Moderately soluble	-4.27	1.70E-02	5.37E-05	Moderately soluble
Molecule 10	1.79E-04	Soluble	-3.85	3.59E-02	1.42E-04	Soluble
Molecule 11	1.11E-04	Soluble	-4.39	1.16E-02	4.03E-05	Moderately soluble
Molecule 12	1.85E-05	Moderately soluble	-4.31	1.50E-02	4.90E-05	Moderately soluble
Molecule 13	1.85E-05	Moderately soluble	-4.31	1.50E-02	4.90E-05	Moderately soluble
Molecule 14	1.85E-05	Moderately soluble	-4.31	1.50E-02	4.90E-05	Moderately soluble
Molecule 15	2.26E-06	Moderately soluble	-5.15	2.63E-03	7.03E-06	Moderately soluble
Molecule 16	2.54E-05	Moderately soluble	-2.81	4.35E-01	1.53E-03	Soluble
Molecule 17	1.10E-07	Poorly soluble	-5.53	1.26E-03	2.99E-06	Moderately soluble
Molecule 18	1.35E-04	Soluble	-2.87	3.45E-01	1.36E-03	Soluble
Molecule 19	5.78E-06	Moderately soluble	-4.04	2.93E-02	9.08E-05	Moderately soluble

 

 

Table 6. Pharmacokinetics

Molecule No	Pharmacokinetics
	GI absorption	BBB permeant	Pgp substrate	CYP1A2 inhibitor	CYP2C19 inhibitor	CYP2C9 inhibitor	CYP2D6 inhibitor	CYP3A4 inhibitor	log Kp (cm/s)
Molecule 1	Low	No	Yes	No	No	No	No	No	-8.71
Molecule 2	High	Yes	No	Yes	Yes	No	No	No	-5.67
Molecule 3	High	Yes	No	Yes	Yes	No	No	No	-5.74
Molecule 4	High	Yes	No	Yes	Yes	No	No	No	-5.74
Molecule 5	High	Yes	No	Yes	Yes	No	No	No	-5.74
Molecule 6	High	Yes	No	Yes	Yes	No	No	No	-5.74
Molecule 7	High	Yes	No	No	Yes	No	No	No	-5.78
Molecule 8	High	Yes	No	Yes	Yes	Yes	No	No	-5.47
Molecule 9	High	Yes	No	Yes	Yes	Yes	No	No	-5.66
Molecule 10	High	Yes	No	Yes	Yes	No	No	No	-5.8
Molecule 11	High	Yes	No	Yes	Yes	No	No	No	-5.88
Molecule 12	High	Yes	No	Yes	Yes	Yes	No	No	-5.46
Molecule 13	High	Yes	No	Yes	Yes	Yes	No	No	-5.46
Molecule 14	High	Yes	No	Yes	Yes	Yes	No	No	-5.46
Molecule 15	Low	No	No	No	Yes	Yes	No	No	-5.25
Molecule 16	High	No	No	No	Yes	No	No	No	-6.07
Molecule 17	Low	No	No	No	Yes	Yes	No	Yes	-4.78
Molecule 18	High	No	No	Yes	Yes	No	No	No	-6.02
Molecule 19	High	Yes	No	Yes	Yes	Yes	No	No	-5.34

 

Table 7. Drugsimilarity

Molecule No	Drugsimilarity
	Lipinski violations	Ghose violations	Veber violations	Egan violations	Muegge violations	Bioavailability Score
Molecule 1	3	2	1	1	3	0.17
Molecule 2	0	0	0	0	0	0.55
Molecule 3	0	0	0	0	0	0.55
Molecule 4	0	0	0	0	0	0.55
Molecule 5	0	0	0	0	0	0.55
Molecule 6	0	0	0	0	0	0.55
Molecule 7	0	0	0	0	0	0.55
Molecule 8	0	0	0	0	0	0.55
Molecule 9	0	0	0	0	0	0.55
Molecule 10	0	0	0	0	0	0.55
Molecule 11	0	0	0	0	0	0.55
Molecule 12	0	0	0	0	0	0.55
Molecule 13	0	0	0	0	0	0.55
Molecule 14	0	0	0	0	0	0.55
Molecule 15	0	1	0	1	0	0.55
Molecule 16	0	0	0	0	0	0.55
Molecule 17	0	1	0	1	1	0.55
Molecule 18	0	0	0	0	0	0.55
Molecule 19	0	0	0	0	0	0.55

 

Table 8. Medicinal Chemistry

Molecule No	Medicinal Chemistry
	PAINS alerts	Brenk alerts	Leadlikeness violations	Synthetic Accessibility
Molecule 1	1	1	1	5.81
Molecule 2	0	1	1	3.81
Molecule 3	0	1	0	3.83
Molecule 4	0	1	0	3.82
Molecule 5	0	1	0	3.77
Molecule 6	0	1	0	3.77
Molecule 7	0	2	0	3.82
Molecule 8	0	1	1	3.74
Molecule 9	0	1	1	3.79
Molecule 10	0	1	0	3.78
Molecule 11	0	1	0	3.76
Molecule 12	0	1	1	3.8
Molecule 13	0	1	1	3.78
Molecule 14	0	1	1	3.76
Molecule 15	0	1	2	3.91
Molecule 16	0	3	0	3.87
Molecule 17	0	2	2	3.9
Molecule 18	0	1	0	3.76
Molecule 19	0	1	1	3.81

 

CONCLUSION:

In this work, 18 novel fluorinated molecules i.e. 3-Ethyl-5-fluoro-2-phenylimino-thiazolidin-4-one derivatives were evaluated for their in-silico analysis against C-KIT Tyrosine Kinase Protein 1T46. Molecular docking analysis revealed that compounds 13 and 19 were found to be potent moieties. The ADME study revealed that most of the compounds exhibit low adverse effects. These initial findings serve as a lead for the development of more potent and selectively targeted hybrid anticancer drugs.

 

CONFLICT OF INTEREST:

The authors declare that there are no conflict of interests regarding the publication of this article.

 

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Accepted on 15.05.2024           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(9):4559-4568.