Molecular modeling study bioactive natural product of khellin analogues as a novel potential pharmacophore of EGFR inhibitors

Figures & data

Scheme 1.  Reaction of khellin (1) with malononitril gave compound (2) which was examined against P2S5, CS2 and Ac2O in refluxing pyridine.

Scheme 2.  The Reaction Mechanism proposed for the formation of organophosphorus compound (OPC).

Figure 1.  The SAR and EGFR inhibitory activity of the khellin derivatives 1–5.

Figure 2.  The docking score of the tested compounds 1–5.

Figure 3.  Anti-proliferative activity against MCF-7 and Hela for compounds 1–5. The intensity of the developed colour measured by reading optical absorbance at 450 nm using a microplate reader FLUOstar OPTIMA ^a(IC50 compound concentration required to inhibit tumour cell proliferation by 50%. ^bHuman breast cell line (MCF-7). ^cHuman cervix cell line (HELA).

Scheme 3.  The Model compounds of (6a-e), (7a-g) and erlotinib (1M17) (8) which obtained from protein data bank (PDB)58,59.

Figure 4.  Lead compound erlotinib (green colour) (A) and khellin 1 (B): the proposed binding mode of compounds (A) and (B) in the ATP binding site of EGFR resulting from docking Energy is −10.86 and −11.38 respectively. The most important amino acids are shown together with their respective numbers.

Figure 5.  2(A), 5(B) and 4(C): the proposed binding mode of Molecular docking modelling of compounds 2(A), 4(C), 5(B) and 3(E,F) with EGFR kinase: for clarity, only interacting residues are displayed in the ATP binding site of EGFR resulting from docking respectively. The most important amino acids are shown together with their respective numbers. Compound 5 form three hydrogen bonds one acceptors with N-H group of Met769 and two donors one with carboxylate oxygen of Asp 331 and one of the carbonyl oxygen of Lys 721. (D): Alignment of docked compound 5 (purple colour) and erlotinib (green colour) in the ATP binding site of EGFR, shows amino acids in contact in the same position. The H-bond is displayed as line. Compound 5 is nicely bound to the EGFR kinase with its N–H group project toward the side chain carbonyl group of D831 (Asp831), forming a more optimal H-bond interaction. Also, the oxygen atom of the methoxy group of compound C5 forms hydrogen bond with G697 (Gly695).

Figure 6.  The anti-tumour properties of the tested compounds at a dose of 10 mM utilizing human tumour cell lines.