Department of Pharmaceutical Chemistry, PRES, Pravara Rural College of Pharmacy Pravaranagar, Maharashtra 413736, India
Lung tumour is prevalent malignancies in population, with (EGFR) serving as critical therapeutic agent as its treatment due to its pivotal role in tumour progression and survival. The present study hypothesises that 5-(4-bromophenyl)-N-ethyl-1,3,4-thiadiazol-2-amine derivatives exhibit significant binding affinities toward EGFR, thereby representing potential anti-cancer agents. These studies we have Designed thiadiazole analogues gone through “Lipinski's rule of 5”, vebers rule, ADMET screening, drug-likeness. The molecular Docking was conducted via PyRx software to evaluate binding interactions of the synthesised derivatives with EGFR kinase domain. We performed the comparative study of docking between the designed thadiazole derivative and standard anticancer drug erlotinib. We conclude that 26 out of 33 molecule follows Lipinski’s rule of five with zero violation, also all compounds successfully passed toxicity assessment. The docking result conclude that the compound SP22, SP23, SP24, SP25, SP26, SP28, SP29, SP30, SP32 and SP33exhibited highest docking score as compared to standard anticancer drug erlotinib targeting EGFR kinase. Hence these molecules are selected for future synthesis. This study highlights the potential of thiadiazole-based scaffolds in anti-cancer drug design.
Tumour remains threat and life-threatening concerns. Among its various types, lung cancer stands out as particularly deadly. Kinases, a class of enzymes responsible for transferring phosphate groups, play a pivotal role in numerous cellular functions. Among these, cytoplasmic tyrosine kinases are crucial for transmitting external signals into the cell and are often associated with oncogenic processes. As a result, developing inhibitors that specifically target tyrosine kinases is critically important in cancer treatment [1-3].
The development of several strong and TKIs, past 20 years has advanced our knowledge. A molecular target for certain possible cancer treatments has been found to be EGFR. Thirteen secreted polypeptide ligands and EGFR family [4-5].
To address these challenges, extensive research has been conducted to design innovative EGFR inhibitors with enhanced selectivity and efficacy. Among the different chemical frameworks studied, thiadiazole derivatives have shown great promise as biological properties. Modifications such as halogenation and N-methylation have been found to significantly improve their pharmacological activity, particularly against kinases like EGFR[6-8].
In Present study we have to performed computational methodologies. It plays vital role in drug discovery and to minimize the risk of toxicity. In this study, we propose that 5-(4-bromophenyl)-N-ethyl-1, 3, 4-thiadiazol-2-amine derivatives exhibit strong EGFR inhibitory activity through specific interactions within the kinase domain. Molecular docking analysis was employed to evaluate their binding affinities, interaction mechanisms, and structural features. This research aims to identify novel and selective EGFR inhibitors, contributing to the advancement of targeted lung cancer therapies [9].
The standard anticancer drug erlotinib, a tyrosine kinase inhibitor used in the treatment of non-small cell lung cancer and pancreatic cancer, was used for a comparative study with thiadiazole derivatives. The study was conducted based on their binding affinity to the EGFR kinase protein, a key target in cancer therapy[10
MATERIAL AND METHODS
Designing of 5-(4-bromophenyl)-N-ethyl-1, 3, 4-thiadiazole-2-amine derivatives
The reaction was achieved by ethyl 4-bromobenzoate react with hydrazine hydrochloride (NH2 NH2.HCL) in ethanol under reflux condition to form 4bromobenzohydrazide. Further 4bromobenzohydrazide treated with thiocyanate in ethanol under reflux condition to give 2-[(4-bromophenyl) carbonyl]-N-ethylhydrazinecarbothioamide, further 2-[(4-bromophenyl) carbonyl]-N-ethylhydrazinecarbothioamide is react with concentrated sulphuric acid (H2SO4) with continuous stirring to form 5(4-bromophenyl)-N-ethyl-1,3,4-thiadiazole-2-amine derivatives.
Design scheme: Synthesis of 5-(4-bromophenyl)-N-ethyl-1, 3, 4-thiadiazol-2-amine
Pharmacokinetic and toxicity prediction of designed derivatives
Drug discovery and development heavily relies on chemical ADMET. Also being sufficiently effective against target, drug candidate should have suitable ADMET characteristics at therapeutic dosage. The ADME analysis, drug-likeness, and toxicity parameters of the proposed compounds were evaluated. Swiss ADME servers were used to examine the pharmacokinetic (ADME) properties of proposed derivatives as well as the Lipinski rule of five. ProTox-II has been used to forecast the chemicals' toxicity [11-12].
Molecular Docking
Binding of analogue in active areas of crystal structures of EGFR kinase (T790M/L858R) (PDB DOI: https://doi.org/10.2210/pdb5EDP/pdb) were investigated utilising an in-silico process, which were obtained from www.pdb.org, the Protein Data Bank service. All compound performed docking by PyRx 0.8. Discovery Studio Visualizer (version19) was used to protein preparation. 3D (X= -60.135585, Y= -7.649423, Z= -25.673) was for used to perform docking. BIOVIA Visualizer gave binding information [13].
RESULT AND DISCUSSION
All compounds having bioavailability evaluated by using “Lipinski's rule of five” for oral route (Table 2). Pharmacokinetics parameter & drug-likeness properties of compounds are examined by swissADME software (Table 3). The “acute toxicity has been predicted along with LD50 (mg/kg)” by ProTox-II (Table 4). The PyRx software (0.8 version) of molecular docking to produce “active Amino acid residues, bond length, category, type, ligand energies, and scores” of compounds [14-15]. The Comparative study was performed by using standard anticancer drug (Erlotinib) with binding protein EGFR kinase (Table 5-6).
Table 1: Structure, IUPAC name and Molecular formula
|
Comp.Code |
Structure |
IUPAC Name |
M.F |
|
SP1 |
|
5-(4-bromophenyl)-N-ethyl-1,3,4-thiadiazol-2-amine
|
C10H10BrN3S |
|
SP2 |
|
5-(4-bromophenyl)-N-propyl-1,3,4-thiadiazol-2-amine
|
C11H12BrN3S |
|
SP3 |
|
5-(4-bromophenyl)-N-(propan-2-yl)-1,3,4-thiadiazol-2-amine
|
C11H12BrN3S |
|
SP4 |
|
5-(4-bromophenyl)-N-butyl-1,3,4-thiadiazol-2-amine
|
C12H14BrN3S |
|
SP5 |
|
5-(4-bromophenyl)-N-(2-methylpropyl)-1,3,4-thiadiazol-2-amine
|
C12H14BrN3S |
|
SP6 |
|
5-(4-bromophenyl)-N-(butan-2-yl)-1,3,4-thiadiazol-2-amine
|
C12H14BrN3S |
|
SP7 |
|
5-(4-bromophenyl)-N-tert-butyl-1,3,4-thiadiazol-2-amine
|
C12H14BrN3S |
|
SP8 |
|
5-(4-bromophenyl)-N-pentyl-1,3,4-thiadiazol-2-amine
|
C13H16BrN3S |
|
SP9 |
|
5-(4-bromophenyl)-N-(3-methylbutyl)-1,3,4-thiadiazol-2-amine |
C13H16BrN3S |
|
SP10 |
|
5-(4-bromophenyl)-N-(2,2-dimethylpropyl)-1,3,4-thiadiazol-2-amine
|
C13H16BrN3S |
|
SP11 |
|
5-(4-bromophenyl)-N-hexyl-1,3,4-thiadiazol-2-amine
|
C14H18BrN3S |
|
SP12 |
|
5-(4-bromophenyl)-N-heptyl-1,3,4-thiadiazol-2-amine
|
C15H20BrN3S |
|
SP13 |
|
5-(4-bromophenyl)-N-octyl-1,3,4-thiadiazol-2-amine
|
C16H22BrN3S |
|
SP14 |
|
5-(4-bromophenyl)-N-nonyl-1,3,4-thiadiazol-2-amine
|
C17H24BrN3S |
|
SP15 |
|
5-(4-bromophenyl)-N-decyl-1,3,4-thiadiazol-2-amine
|
C18H26BrN3S |
|
SP16 |
|
5(4-bromophenyl)-N-undecyl-1,3,4-thiadiazole-2-amine
|
C19H28BrN3S |
|
SP17 |
|
5(4-bromophenyl)-N-dodecyl-1,3,4-thiadiazole-2-amine |
C20H30BrN3S |
|
SP18 |
|
5(4-bromophenyl)-N-tridecyl-1,3,4- thiadiazole-2-amine |
C21H32BrN3S |
|
SP19 |
|
5(4-bromophenyl)-N-tetradecyl-1,3,4- thiadiazole-2-amine |
C22H34BrN3S |
|
SP20 |
|
5(4-bromophenyl)-N-pentadecyl-1,3,4-thiadiazole-2-amine
|
C23H36BrN3S |
|
SP21 |
|
5-(4-bromophenyl)-N-phenyl-1,3,4-thiadiazol-2-amine
|
C14H10BrN3S |
|
SP22 |
|
5-(4-bromophenyl)-N-(2-methylphenyl)-1,3,4-thiadiazol-2-amine
|
C15H11BrN3S |
|
SP23 |
|
5-(4-bromophenyl)-N-(3-methylphenyl)-1,3,4-thiadiazol-2-amine
|
C15H11BrN3S |
|
SP24 |
|
5-(4-bromophenyl)-N-(4-methylphenyl)-1,3,4-thiadiazol-2-amine
|
C15H11BrN3S |
|
SP25 |
|
5-(4-bromophenyl)-N-(2-chlorophenyl)-1,3,4-thiadiazol-2-amine
|
C14H9BrN3SCl |
|
SP26 |
|
5-(4-bromophenyl)-N-(3-chlorophenyl)-1,3,4-thiadiazol-2-amine
|
C14H9BrN3SCl |
|
SP27 |
|
5-(4-bromophenyl)-N-(4-chlorophenyl)-1,3,4-thiadiazol-2-amine
|
C14H9BrN3SCl |
|
SP28 |
|
5-(4-bromophenyl)-N-(2-nitrophenyl)-1,3,4-thiadiazol-2-amine
|
C14H9BrN4SO2 |
|
SP29 |
|
5-(4-bromophenyl)-N-(3-nitrophenyl)-1,3,4-thiadiazol-2-amine
|
C14H9BrN4SO2 |
|
SP30 |
|
5-(4-bromophenyl)-N-(4-nitrophenyl)-1,3,4-thiadiazol-2-amine
|
C14H9BrN4SO2 |
|
SP31 |
|
5-(4-bromophenyl)-N-(2-methoxyphenyl)-1,3,4-thiadiazol-2-amine
|
C15H12BrN3SO |
|
SP32 |
|
5-(4-bromophenyl)-N-(3-methoxyphenyl)-1,3,4-thiadiazol-2-amine
|
C15H12BrN3SO |
|
SP33 |
|
5-(4-bromophenyl)-N-(4-methoxyphenyl)-1,3,4-thiadiazol-2-amine
|
C15H12BrN3SO |
Where: IUPAC – International Union of Pure and Applied Chemistry, MF – Molecular Formula
Table 2: Lipinski rule of 5, Veber’s rule
|
Compound Code |
Lipinski rule of five |
Veber’s rule |
|||||
|
MW |
Log P |
HBA |
HBD |
Lipinski violation |
TPSA |
Rotatable Bond |
|
|
SP1 |
284.18 |
2.76 |
2 |
1 |
0 |
66.05 |
3 |
|
SP2 |
298.2 |
2.99 |
2 |
1 |
0 |
66.05 |
4 |
|
SP3 |
298.2 |
2.95 |
2 |
1 |
0 |
66.05 |
3 |
|
SP4 |
312.23 |
3.13 |
2 |
1 |
0 |
66.05 |
5 |
|
SP5 |
312.23 |
3.25 |
2 |
1 |
0 |
66.05 |
4 |
|
SP6 |
312.23 |
3.22 |
2 |
1 |
0 |
66.05 |
4 |
|
SP7 |
312.23 |
3.08 |
2 |
1 |
0 |
66.05 |
3 |
|
SP8 |
326.26 |
3.32 |
2 |
1 |
0 |
66.05 |
6 |
|
SP9 |
326.26 |
3.41 |
2 |
1 |
0 |
66.05 |
5 |
|
SP10 |
326.26 |
3.41 |
2 |
1 |
0 |
66.05 |
4 |
|
SP11 |
340.28 |
3.68 |
2 |
1 |
0 |
66.05 |
7 |
|
SP12 |
354.31 |
3.82 |
2 |
1 |
0 |
66.05 |
8 |
|
SP13 |
368.33 |
4.13 |
2 |
1 |
0 |
66.05 |
9 |
|
SP14 |
382.36 |
4.4 |
2 |
1 |
1 |
66.05 |
10 |
|
SP15 |
396.39 |
4.76 |
2 |
1 |
1 |
66.05 |
11 |
|
SP16 |
410.41 |
4.83 |
2 |
1 |
1 |
66.05 |
12 |
|
SP17 |
424.44 |
5.08 |
2 |
1 |
1 |
66.05 |
13 |
|
SP18 |
438.47 |
5.22 |
2 |
1 |
1 |
66.05 |
14 |
|
SP19 |
452.49 |
5.49 |
2 |
1 |
1 |
66.05 |
15 |
|
SP20 |
466.52 |
5.73 |
2 |
1 |
1 |
66.05 |
16 |
|
SP21 |
332.22 |
2.89 |
2 |
1 |
0 |
66.05 |
3 |
|
SP22 |
346.24 |
3.07 |
2 |
1 |
0 |
66.05 |
3 |
|
SP23 |
346.24 |
3.17 |
2 |
1 |
0 |
66.05 |
3 |
|
SP24 |
346.24 |
3.15 |
2 |
1 |
0 |
66.05 |
3 |
|
SP25 |
366.66 |
3.35 |
2 |
1 |
0 |
66.05 |
3 |
|
SP26 |
366.66 |
3.26 |
2 |
1 |
0 |
66.05 |
3 |
|
SP27 |
366.66 |
3.18 |
2 |
1 |
0 |
66.05 |
3 |
|
SP28 |
377.22 |
2.61 |
4 |
1 |
0 |
111.87 |
4 |
|
SP29 |
377.22 |
2.64 |
4 |
1 |
0 |
111.87 |
4 |
|
SP30 |
377.22 |
2.54 |
4 |
1 |
0 |
111.87 |
4 |
|
SP31 |
362.24 |
3.44 |
3 |
1 |
0 |
75.28 |
4 |
|
SP32 |
362.24 |
3.21 |
3 |
1 |
0 |
75.28 |
4 |
|
SP33 |
362.24 |
3.23 |
3 |
1 |
0 |
75.28 |
4 |
Where: MW- Molecular Weight, HBA - Number of hydrogen bond acceptors, HBD - Number of hydrogen bond donor, TPSA – Total Polar Surface area, Log p - logarithm of compound partition.
Table 3: the pharmacokinetics and drug-likeness Properties of Compound
|
Code |
GI absor ption |
BBB PERMEANT |
Pgp substrate |
CYP1A2 inhibitor |
CYP2C19 inhibitor |
CYP2C9 inhibitor |
CYP2D6 inhibitor |
CYP3A4 inhibitor |
Ghose
|
Veber
|
Egan
|
Muegge |
Bioavailability score |
|
SP1 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP2 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP3 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP4 |
High |
Yes |
No |
Yes |
Yes |
Yes |
Yes |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP5 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP6 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP7 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP8 |
High |
Yes |
No |
Yes |
Yes |
Yes |
Yes |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP9 |
High |
Yes |
No |
Yes |
Yes |
Yes |
Yes |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP10 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP11 |
High |
Yes |
No |
Yes |
Yes |
Yes |
Yes |
Yes |
0 |
0 |
0 |
1 |
0.55 |
|
SP12 |
High |
No |
No |
Yes |
Yes |
Yes |
Yes |
Yes |
0 |
0 |
0 |
1 |
0.55 |
|
SP13 |
High |
No |
No |
Yes |
Yes |
Yes |
Yes |
Yes |
0 |
0 |
0 |
1 |
0.55 |
|
PS14 |
High |
No |
No |
Yes |
Yes |
Yes |
Yes |
Yes |
1 |
0 |
1 |
1 |
0.55 |
|
SP15 |
High |
No |
No |
No |
Yes |
Yes |
Yes |
Yes |
1 |
1 |
1 |
1 |
0.55 |
|
SP16 |
High |
No |
No |
No |
Yes |
Yes |
Yes |
Yes |
1 |
1 |
1 |
1 |
0.55 |
|
SP17 |
Low |
No |
Yes |
No |
Yes |
Yes |
No |
Yes |
1 |
1 |
1 |
1 |
0.55 |
|
SP18 |
Low |
No |
Yes |
No |
Yes |
No |
NO |
Yes |
1 |
1 |
1 |
1 |
0.55 |
|
SP19 |
Low |
No |
Yes |
No |
Yes |
No |
NO |
Yes |
1 |
1 |
1 |
1 |
0.55 |
|
SP20 |
Low |
No |
Yes |
No |
Yes |
No |
NO |
Yes |
1 |
1 |
1 |
2 |
0.55 |
|
SP21 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
Yes |
0 |
0 |
0 |
0 |
0.55 |
|
SP22 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
Yes |
0 |
0 |
0 |
0 |
0.55 |
|
SP23 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
Yes |
0 |
0 |
0 |
0 |
0.55 |
|
SP24 |
High |
Yes |
No |
Yes |
Yes |
Yes |
No |
Yes |
0 |
0 |
0 |
0 |
0.55 |
|
SP25 |
High |
No |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
1 |
0.55 |
|
SP26 |
High |
No |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
1 |
0.55 |
|
SP27 |
High |
No |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
1 |
0.55 |
|
SP28 |
High |
No |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP29 |
High |
No |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP30 |
High |
No |
No |
Yes |
Yes |
Yes |
No |
No |
0 |
0 |
0 |
0 |
0.55 |
|
SP31 |
High |
No |
No |
Yes |
Yes |
Yes |
Yes |
Yes |
0 |
0 |
0 |
0 |
0.55 |
|
SP32 |
High |
No |
No |
Yes |
Yes |
Yes |
Yes |
Yes |
0 |
0 |
0 |
0 |
0.55 |
|
SP33 |
High |
No |
No |
Yes |
Yes |
Yes |
Yes |
Yes |
0 |
0 |
0 |
0 |
0.55 |
Where: GI - gastrointestinal absorption, BBB- blood brain barrier penetration; P-gp - p-glycoprotein
Table 4: The acute toxicity of Compounds
|
COMP. CODE |
LD50 (mg/kg) |
Toxicity class |
Prediction Accuracy (%) |
Hepatotoxicity |
Carcinogenicity |
Immunotoxicity |
Mutagenicity |
Cytotoxicity |
|
SP1 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP2 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP3 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP4 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP5 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP6 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP7 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP8 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP9 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP10 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP11 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP12 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP13 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP14 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP15 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP16 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP17 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP18 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP19 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP20 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP21 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP22 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP23 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP24 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP25 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP26 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP27 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP28 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP29 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP30 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP31 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP32 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
|
SP33 |
1190 |
4 |
100 |
A (0.69) |
I (0.62) |
A (0.96) |
I (0.97) |
I (0.93) |
Where: I- Inactive, A - Active
Table 5: Standard Erlotinib Docking Score and 2D, 3D Images
|
CODE |
ACTIVE AMINO ACID |
BOND TYPE |
DOCKING SCORE |
2D IMAGE |
3D IMAGE |
|
Erlotinib |
CYS797 |
Conventional Hydrogen Bond |
-6.8 |
|
|
|
CYS797 |
|||||
|
ARG841 |
Carbon Hydrogen Bond |
||||
|
LEU718 |
Pi-Sigma |
||||
|
LEU844 |
|||||
|
MET790 |
Pi-Sulfur |
||||
|
LEU718 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
LEU844 |
Table 6: Derivatives Docking Score and 2D, 3D Images
|
CODE |
ACTIVE AMINO ACID |
BOND TYPE |
DOCKING SCORE |
2D Image |
3D Image |
|
SP1 |
LEU778 |
Conventional Hydrogen Bond |
-5.8 |
|
|
|
ILE1018 |
Pi-Cation |
||||
|
ARG776 |
Pi-Anion |
||||
|
LEU778 |
|||||
|
ILE1018 |
Pi-Sigma |
||||
|
ARG776 |
Alkyl |
||||
|
LEU778 |
Pi-Alkyl |
||||
|
SP2 |
LEU844 |
Pi-Sigma |
-5.8 |
|
|
|
PHE723 |
|||||
|
ALA743 |
Alkyl |
||||
|
LEU718 |
|||||
|
LEU792 |
|||||
|
VAL726 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
SP3 |
ASP1014 |
Conventional Hydrogen Bond |
-6.3 |
|
|
|
ARG705 |
Carbon Hydrogen Bond |
||||
|
ARG776 |
Pi-Cation |
||||
|
ARG705 |
Alkyl |
||||
|
PRO772 |
|||||
|
ALA1013 |
Pi-Alkyl |
||||
|
SP4 |
LEU778 |
Carbon Hydrogen Bond |
-6.2 |
|
|
|
ARG776 |
Pi-Cation |
||||
|
ASP1014 |
Pi-Anion |
||||
|
LEU778 |
Pi-Sigma |
||||
|
ARG705 |
Alkyl |
||||
|
ILE1018 |
|||||
|
LEU703 |
|||||
|
ARG705 |
|||||
|
ILE1018 |
|||||
|
ALA1013 |
Pi-Alkyl |
||||
|
ARG776 |
|||||
|
SP5 |
ASP1014 |
Conventional Hydrogen Bond |
-6.2 |
|
|
|
ARG705 |
Carbon Hydrogen Bond |
||||
|
ARG776 |
Pi-Cation |
||||
|
ARG705 |
Alkyl |
||||
|
PRO772 |
|
||||
|
ALA1013 |
Pi-Alkyl |
||||
|
SP6 |
ALA1013 |
Conventional Hydrogen Bond |
-6.3 |
|
|
|
ARG776 |
Pi-Cation |
||||
|
LEU703 |
Alkyl |
||||
|
ARG705 |
|||||
|
ARG776 |
|||||
|
LEU778 |
Pi-Alkyl |
||||
|
LEU1017 |
|||||
|
ARG705 |
|||||
|
SP7 |
ASP1014 |
Conventional Hydrogen Bond |
-6.1 |
|
|
|
ARG705 |
Carbon Hydrogen Bond |
||||
|
ARG776 |
Pi-Cation |
||||
|
LEU1017 |
Pi-Sigma |
||||
|
ARG705 |
Alkyl |
||||
|
SP8 |
ARG705 |
Carbon Hydrogen Bond |
-6.1 |
|
|
|
ASP770 |
|||||
|
ARG776 |
Pi-Cation |
||||
|
PRO772 |
Alkyl |
||||
|
ARG705 |
|||||
|
PRO772 |
|||||
|
HIS850 |
Pi-Alkyl |
||||
|
ALA1013 |
|||||
|
SP9 |
LEU778 |
Conventional Hydrogen Bond |
-6.2 |
|
|
|
ARG776 |
Pi-Cation |
||||
|
ASP770 |
Pi-Anion Pi-Anion |
||||
|
ASP1014 |
|||||
|
LEU778 |
Pi-Sigma |
||||
|
ILE1018 |
Alkyl |
||||
|
ALA1013 |
Pi-Alkyl |
||||
|
ARG776 |
|||||
|
SP10 |
MET793 |
Conventional Hydrogen Bond |
-5.9 |
|
|
|
LEU718 |
Pi-Sigma
|
||||
|
LEU718 |
|||||
|
MET790 |
Alkyl
|
||||
|
LEU844 |
|||||
|
ALA743 |
Pi-Alkyl |
||||
|
SP11 |
LEU844 |
Pi-Sigma |
-6.1 |
|
|
|
MET790 |
Pi-Sulfur |
||||
|
ALA743 |
Alkyl |
||||
|
ILE759 |
|||||
|
LEU718 |
|||||
|
LEU792 |
|||||
|
PHE723 |
Pi-Alkyl |
||||
|
PHE723 |
|||||
|
VAL726 |
|||||
|
ALA743 |
|||||
|
SP12 |
LYS745 |
Pi-Cation; Pi-Donor Hydrogen Bond |
-6.1 |
|
|
|
LEU844 |
Pi-Sigma |
||||
|
MET790 |
Pi-Sulfur |
||||
|
ALA743 |
Alkyl |
||||
|
ILE759 |
|||||
|
LEU718 |
|||||
|
PHE723 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
SP13 |
LYS745 |
Pi-Cation;Pi-Donor Hydrogen Bond |
-6.2 |
|
|
|
LEU844 |
Pi-Sigma |
||||
|
MET766 |
Pi-Sulfur |
||||
|
MET790 |
|||||
|
ALA743 |
Alkyl |
||||
|
LEU747 |
|||||
|
ILE759 |
|||||
|
LEU718 |
|||||
|
VAL726 |
|||||
|
VAL726 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
SP14 |
GLU758 |
Conventional Hydrogen Bond |
-5.7 |
|
|
|
ASP761 |
Pi-Anion |
||||
|
LEU747 |
Alkyl Alkyl |
||||
|
ILE759 |
|||||
|
PHE723 |
Pi-Alkyl |
||||
|
SP15 |
ARG776 |
Pi-Cation |
-6.0 |
|
|
|
ASP770 |
Pi-Anion
|
||||
|
ASP1014 |
|||||
|
LEU778 |
Pi-Sigma |
||||
|
ARG705 |
Alkyl |
||||
|
ILE1018 |
|||||
|
LEU703 |
|||||
|
ALA1013 |
Pi-Alkyl |
||||
|
ARG776 |
|||||
|
SP16 |
SER912 |
Conventional Hydrogen Bond |
-6.1 |
|
|
|
PRO934 |
Alkyl |
||||
|
PRO934 |
|||||
|
PRO934 |
|||||
|
LEU933 |
|||||
|
PRO934 |
|||||
|
TRP905 |
Pi-Alkyl |
||||
|
TRP905 |
|||||
|
PHE910 |
|||||
|
TYR915 |
|||||
|
SP17 |
LEU718 |
Pi-Sigma |
-5.4 |
|
|
|
LEU718 |
|||||
|
VAL726 |
Alkyl |
||||
|
VAL726 |
|||||
|
ALA743 |
|||||
|
CYS797 |
|||||
|
MET790 |
|||||
|
LEU718 |
|||||
|
PHE723 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
LEU844 |
|||||
|
SP18 |
ALA1013 |
Conventional Hydrogen Bond |
-5.9 |
|
|
|
ASP770 |
Pi-Anion |
||||
|
ASP1014 |
|||||
|
ASP1014 |
Pi-Sigma |
||||
|
LEU778 |
Alkyl |
||||
|
PRO772 |
|||||
|
ILE1018 |
|||||
|
ILE1018 |
|||||
|
LEU703 |
|||||
|
ARG705 |
|||||
|
ILE1018 |
|||||
|
TYR1016 |
Pi-Alkyl |
||||
|
PRO772 |
|||||
|
SP19 |
GLU758 |
Conventional Hydrogen Bond |
-5.9 |
|
|
|
ASP761 |
Pi-Anion |
||||
|
LEU747 |
Alkyl |
||||
|
ILE759 |
|||||
|
PHE723 |
Pi-Alkyl |
||||
|
PHE723 |
|||||
|
SP20 |
SER912 |
Conventional Hydrogen Bond |
-5.7 |
|
|
|
PRO934 |
Alkyl |
||||
|
PRO934 |
|||||
|
PRO934 |
|||||
|
PRO934 |
|||||
|
ILE981 |
|||||
|
TRP905 |
Pi-Alkyl |
||||
|
TRP905 |
|||||
|
PHE910 |
|||||
|
TYR915 |
|||||
|
SP21 |
ARG776 |
Conventional Hydrogen Bond |
-6.6 |
|
|
|
ASP770 |
Pi-Anion |
||||
|
ASP1014 |
|||||
|
LEU1017 |
Pi-Sigma |
||||
|
PRO772 |
Alkyl |
||||
|
LEU778 |
Pi-Alkyl |
||||
|
SP22 |
LYS745 |
Conventional Hydrogen Bond |
-6.9 |
|
|
|
ASP855 |
Pi-Anion |
||||
|
LEU844 |
Pi-Sigma |
||||
|
MET790 |
Pi-Sulfur |
||||
|
PHE723 |
Pi-Pi Stacked |
||||
|
ALA743 |
Alkyl |
||||
|
MET793 |
|||||
|
VAL726 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
SP23 |
ARG776 |
Conventional Hydrogen Bond |
-7.2 |
|
|
|
ASP770 |
Pi-Anion |
||||
|
LEU1017 |
Alkyl |
||||
|
ILE1018 |
|||||
|
PRO772 |
|||||
|
ALA1013 |
Pi-Alkyl |
||||
|
SP24 |
ARG776 |
Conventional Hydrogen Bond |
-7.0 |
|
|
|
ARG705 |
Carbon Hydrogen Bond |
||||
|
ARG776 |
Pi-Cation |
||||
|
PRO772 |
Alkyl |
||||
|
ILE1018 |
|||||
|
ALA1013 |
Pi-Alkyl |
||||
|
PRO772 |
|||||
|
SP25 |
LEU778 |
Conventional Hydrogen Bond |
-7.6 |
|
|
|
ARG776 |
Pi-Cation |
||||
|
ASP770 |
Pi-Anion |
||||
|
ASP1014 |
|||||
|
LEU778 |
Pi-Sigma |
||||
|
ALA1013 |
Pi-Alkyl |
||||
|
ARG705 |
|||||
|
ARG776 |
|||||
|
SP26 |
LEU718 |
Pi-Sigma |
-6.8 |
|
|
|
LEU844 |
|||||
|
MET790 |
Pi-Sulfur |
||||
|
MET766 |
Alkyl |
||||
|
MET790 |
|||||
|
LEU718 |
|||||
|
LEU718 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
LEU844 |
|||||
|
SP27 |
ASP1012 |
Pi-Anion |
-6.7 |
|
|
|
THR847 |
Pi-Sigma |
||||
|
PHE997 |
Pi-Sulfur |
||||
|
PHE997 |
Pi-Pi T-shaped |
||||
|
PRO992 |
Alkyl |
||||
|
LEU792 |
|
||||
|
PRO794 |
|||||
|
PRO992 |
|||||
|
PRO741 |
Pi-Alkyl |
||||
|
PRO794 |
|||||
|
SP28 |
LEU718 |
Pi-Sigma |
-7.1 |
|
|
|
LEU718 |
Alkyl |
||||
|
LEU718 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
LEU844 |
|||||
|
VAL726 |
|||||
|
MET790 |
|||||
|
SP29 |
LYS745 |
Pi-Cation |
-7.3 |
|
|
|
ASP855 |
Pi-Anion |
||||
|
LEU844 |
Pi-Sigma |
||||
|
PHE723 |
Pi-Pi Stacked |
||||
|
VAL726 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
MET790 |
|||||
|
SP30 |
LYS745 |
Conventional Hydrogen Bond |
-7.1 |
|
|
|
THR854 |
|||||
|
ASP855 |
|||||
|
LEU718 |
Pi-Sigma |
||||
|
LEU718 |
Alkyl |
||||
|
LEU718 |
Pi-Alkyl |
||||
|
ALA743 |
|||||
|
LEU844 |
|||||
|
VAL726 |
|||||
|
MET790 |
|||||
|
LEU844 |
|||||
|
SP31 |
ASP855 |
Conventional Hydrogen Bond |
-6.4 |
|
|
|
GLU762 |
Carbon Hydrogen Bond |
||||
|
LYS745 |
Pi-Cation |
||||
|
LYS745 |
|||||
|
GLU762 |
Pi-Anion |
||||
|
PHE723 |
Pi-Sulfur |
||||
|
PHE723 |
Pi-Pi Stacked |
||||
|
PHE723 |
Pi-Pi T-shaped |
||||
|
ALA755 |
Alkyl |
||||
|
MET766 |
|||||
|
SP32 |
ALA1013 |
Conventional Hydrogen Bond |
-6.9 |
|
|
|
ASP1014 |
Carbon Hydrogen Bond |
||||
|
ARG705 |
Pi-Cation |
||||
|
ARG776 |
|||||
|
ARG776 |
|||||
|
LYS852 |
|||||
|
ASP770 |
Pi-Anion |
||||
|
ASP1014 |
|||||
|
LEU703 |
Alkyl |
||||
|
ARG705 |
|||||
|
ILE1018 |
|||||
|
LEU1017 |
Pi-Alkyl |
||||
|
ARG776 |
|||||
|
ARG705 |
|||||
|
SP33 |
LEU718 |
Pi-Sigma |
-6.9 |
|
|
|
LEU844 |
|||||
|
MET790 |
Pi-Sulfur |
||||
|
LEU718 |
Pi-Alkyl |
||||
|
ALA743 |
Where: 2D-Two Dimension, 3D – Three Dimension
CONCLUSION
In this Present work, we designed a series of 33 thiadiazole derivatives as potential anticancer agents targeting EGFR kinase. The ADMET analysis revealed that 26 out of 33 molecules adhered to Lipinski’s rule of five with zero violations, indicating their potential as drug-like candidates. Furthermore, all compounds successfully passed the toxicity assessment, suggesting favourable pharmacokinetic and safety profiles.
Molecular docking studies were conducted to evaluate the binding affinity of these thiadiazole derivatives against the EGFR kinase. The docking results demonstrated that compounds SP22, SP23, SP24, SP25, SP26, SP28, SP29, SP30, SP32, and SP33 exhibited higher docking scores compared to the standard anticancer drug Erlotinib, suggesting their potential as promising EGFR inhibitors. These findings indicate that selected thiadiazole derivatives could serve as potential lead compounds for further in vitro and in vivo investigations, aiming to develop novel anticancer agents targeting EGFR
ACKNOWLEDGEMENTS
We special thanks to the principal of Pravara Rural College of Pharmacy, Pravaranagar for the providing the facilities for research work.
REFERENCES
Sagar Magar*, Amol Dighe, Manisha Sonawane, Nilima Wani, Pradnya Bawake, Shainesh Bhosale, Designing, In Silico Screening and Molecular Docking Studies of Some Novel 5-(4-Bromophenyl)-N-Ethyl-1,3,4-Thiadiazol-2-Amine Derivatives Targeting EGFR Kinase, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 6, 4038-4055. https://doi.org/10.5281/zenodo.15732309
10.5281/zenodo.15732309
