Inhibition of DNA Topoisomerase Type IIα (TOP2A) by Mitoxantrone and Its Halogenated Derivatives: A Combined Density Functional and Molecular Docking Study

Table 3

Binding energy and nonbonding interaction of mitoxantrone and its derivatives.

Compound	Docking against human topoisomerase II alpha (TOP2A)
	Binding energy (kcal mol^−1)	H-bond		Halogen bond		Hydrophobic interaction		Electrostatic interaction
		Amino acid-ligand atom	Distance (Å)	Amino acid-ligand atom	Distance (Å)	Amino acid-ligand atom	Distance (Å)	Amino acid-ligand atom	Distance (Å)
Mitoxantrone (D)	−9.2	Lys723 [N-H⋯O]; Ile856 [C-O⋯H]; Asp710 [C-O⋯H]; Ile856 [C-O⋯H]; Asp710 [C-O⋯H]	2.2693; 3.0872; 2.9119; 3.0135; 2.2831			Lys723 [alkyl-pi]; Lys723 [alkyl-pi]	4.8912; 4.8521
D1	−9.5	Glu712 [C-O⋯H]; Glu839 [C-O⋯H]; His1005 [C-O⋯H]; Val1006 [C-O⋯H]; Glu839 [C-O⋯H]; His1005 [C-O⋯H]; Glu712 [C-O⋯H ]	2.8309; 2.4579; 2.8559; 2.1817; 2.7366; 2.7720; 2.6202	Ile715 [C-O⋯F]	3.6260	Phe1003 [pi-pi staked]	4.7087	Glu839 [anion-pi]	3.9962
D2	−9.4	Lys723 [N-H⋯O]; Asp710 [C-H⋯O]; Asp710 [C-H⋯O]	2.2143; 2.9100; 2.2783			Lys723 [alkyl-pi]; Lys723 [alkyl-pi]	4.8686; 4.8569
D3	−9.8	Ser709 [C-H⋯N]; Ser756 [C-H⋯Cl]; Asp545 [C-O⋯H]; His759 [N⋯H]; Glu839 [C-O⋯H]; Gln544 [C-O⋯H]	2.3741; 2.8450; 2.9559; 2.6541; 2.1800; 2.2268			Val836 [alkyl-Cl]; Pro724 [alkyl-pi]; Val836 [alkyl-pi]; His758 [pi-Cl]	4.5719; 4.5000; 5.2539; 5.3149	Lys728 [cation-pi]; Asp831 [anion-pi]	2.2629; 3.5500
D4	−10.3	Asn770 [N-H⋯O]; Asn779 [C-O⋯H-O]; Ile856 [C-O⋯H]; Ile856 [C-O⋯H]; Asp710 [C-O⋯H]; Ile856 [C-O⋯H]	2.3508; 2.4357; 2.9606; 3.0344; 2.5335; 2.4966			Lys723 [sigma-pi]; Lys723 [alkyl-pi]	2.7069; 4.9847	Lys723 [cation-pi]	2.7975
D5	−9.3	Lys723 [N-H⋯O]; Ile856 [C-O⋯H]; Asp710 [C-O⋯H]; Ile856 [C-O⋯H]; Asp710 [C-O⋯H]	2.0085; 2.9432; 2.8721; 2.9262; 2.3241			Lys723 [alkyl-pi]; Lys723 [alkyl-pi]; Tyr757 [pi-Br]	4.6518; 4.9056; 4.8900
D6	−9.9	Asn770 [C-O⋯H-N]; Asn770 [O⋯H-N]; Gly852 [C-O⋯H-O]; Ile856 [C-O⋯H]; Asn710 [C-O⋯H]; Ile856 [C-O⋯H]	2.3828; 2.6450; 2.7306; 2.8943; 2.4152; 2.6609			Lys723 [sigma-pi]; Lys723 [alkyl-pi]	2.6360; 5.1763	Lys723 [cation-pi]; Lys723 [cation-pi]	3.5014; 2.9085
D7	−9.5	Glu839 [C-O⋯H-N]; Val1006 [C-O⋯H-N]; Ser717 [O⋯H]; Glu839 [C-O⋯H]; Val1006 [C-O⋯H]; His1005 [C-O⋯H]	3.0102; 2.9825; 2.6782; 2.7621; 2.2233; 3.0479			Phe1003 [pi-pi stacked]; Pro724 [alkyl-I]; Phe1003 [pi-I]	5.0840; 4.6167; 4.7419	Glu839 [anion-pi]	3.7952
D8	−9.7	Asn770 [C-O⋯H-N]; Asn770 [O⋯H-N]; Gly852 [C-O⋯H]; Ile856 [C-O⋯H]; Asn710 [C-O⋯H]; Ile856 [C-O⋯H]	2.3318; 2.3759; 2.8141; 2.8758; 2.6189; 2.4101			Lys723 [alkyl-pi]; Lys723 [alkyl-pi]	4.2645; 5.3858	Lys723 [cation-pi]; Lys723 [cation-pi]	3.5624; 2.7612
D9	−10.3	Lys723 [N-H⋯O-C]; Ile856 [C-O⋯H]; Asp710 [C-O⋯H]; Ile856 [C-O⋯H]; Asp710 [C-O⋯H]	2.0587; 2.9275; 2.9210; 2.8580; 2.3996	Gly725 [N-H⋯F]; Gly725 [N-H⋯F]; Gly725 [C-H⋯F]	2.9348; 2.6339; 2.2421	Tyr757 [pi-alkyl]; Lys723 [alkyl-pi]; Lys723 [alkyl-pi]	5.1734; 4.7419; 4.9257
D10	−10.0	Arg713 [N-H⋯O-C]; Arg713 [N-H⋯O]; Lys723 [N-H⋯F]; Ser763 [C-O⋯N]; Arg929 [N-H⋯O]; Arg929 [N-H⋯O]; His759 [C-O⋯H]	2.4985; 2.3481; 2.2497; 2.4413; 2.9278; 2.8935; 2.8837	Arg713 [C-O⋯F]	3.3749	Lys723 [alkyl-alkyl]; Lys723 [alky-pi]; Ille856 [alkyl-pi]	4.2984; 5.4568; 5.0991

Nonconventional hydrogen bond.