FMS-like tyrosine kinase-3 (FLT3) inhibitors with better binding affinity and ADMET properties than sorafenib and gilteritinib against acute myeloid leukemia: in silico studies

Figures & data

Table 1. Acceptable range of selected ADMET properties.

Parameters	Significance	Acceptable range	References
SwissADME
Physicochemical properties
MW	Molecular weight (MW). MW is the mass of a given molecule. It is expressed in daltons (Da or u), synonymous with g/mol.	Between 150 and 500 g/mol	(Daina et al., 2017)
nHA	Number of heavy atoms (nHA)	20–70	(Ghose et al., 1999)
HBA	Number of hydrogen bond acceptors (HBA). Entails total nitrogen and oxygen atoms (NorO)	<10	(Daina et al., 2017; Lipinski et al., 2001)
HBD	Number of hydrogen bond donors (HBD). Entails total N–H and O–H bonds (NHorOH). Too many HBD can lead to low-fat solubility.	<5	(Daina et al., 2017; Lipinski et al., 2001)
MR	Molecular refractivity (MR). MR is dependent on temperature, pressure, and index of refraction. It represents a measure of the total polarizability of a mole of a substance.	40–130	(Ghose et al., 1999)
TPSA	Topological polar surface area (TPSA). TPSA is the surface sum of all polar atoms. It predicts the ability of compounds to permeate cell membranes. TPSA above 140 Å^2 is considered poor.	Between 20 and 130 Å^2	(Daina et al., 2017)
ROTBs	Number of rotatable bonds (ROTBs). Entails flexibility	< 9	(Daina et al., 2017)
Lypophilicity
Log PO/W	Log PO/W is the consensus arithmetic mean of five proposed methods.	−0.7 and +5.0 for XLOGP3	(Daina et al., 2017)
Water solubility
Log S	Decimal logarithm of the molar solubility in water (Log S).	< 6	(Daina et al., 2017)
Druglikeness
Lipinski’s rule of 5	According to Lipinski et al. (2001), an oral drug candidate must not violate more than 1 of the following rules (applied above): Should not be >5 hydrogen bond donors (the total number of nitrogen–hydrogen and oxygen-hydrogen bonds). Should not be >10 hydrogen bond acceptors (all nitrogen or oxygen atoms). Molecular mass should be <500 daltons. The octanol-water partition coefficient (log P) should not be >5	YES if there is any violation and NO if there is none.	(Daina et al., 2017)
pkCMS
Absorption
Caco-2	Caco-2 predicts the absorption rate of oral drugs in the intestinal mucosa	High if >0.90	(Pires et al., 2015)
Intestinal absorbance	Intestinal absorbance predicts the percentage to be absorbed	Poor if <30%	(Pires et al., 2015)
P-gp I and II inhibitors	P-glycoprotein (P-gp), an ATP-binding cassette transporter works to remove xenobiotics out of cells. This model predicts if a compound is likely to be its inhibitor or not.	Inhibits P-gp I or II, both or none	(Pires et al., 2015)
Distribution
BBB	Blood-brain barrier (BBB) protects the brain from exogenous compounds	Compounds with LogBB > 0.3 can cross the BBB while those with logBB < −1 would be poorly distributed	(Pires et al., 2015)
CNS	The central nervous system (CNS) permeability model measures the blood-brain permeability surface area product (logPS)	Compounds with logPS > −2 can penetrate the CNS while those with logPS < −3 would be unable	(Pires et al., 2015)
Metabolism
CYP2D6	Cytochrome P450 works by detoxifying drugs and xenobiotics. CYP2D6 metabolize ≈ 25% of drugs (Wang et al., 2009)	YES or NO if the compound will be metabolized by CYP2D6	(Pires et al., 2015)
CYP3A4	CYP3A4 metabolize ≈ half of 60% of drugs credited to cytochrome P450 (Zanger & Schwab, 2013)	YES or NO if the compound will be metabolized by CYP3A4
Excretion
TC	Total clearance (TC) is a predictor of both hepatic and renal clearance. It is a measure of proportionality constant CLtot.	Measured in log (ml/min/kg)	(Pires et al., 2015)
Toxicity
Ames	Ames toxicity measures the ability of a compound to be mutagenic.	YES or NO	(Pires et al., 2015)
MRTD	Maximum recommended tolerated dose (MRTD) gives an estimate of the toxic threshold of chemicals in humans.	MRTD ≤0.477 is low while ≥0.477 is high	(Pires et al., 2015)
LD50	LD50 is the amount of dose capable of causing death in 50% of test animals.	Predicts LD50 in mol/kg	(Pires et al., 2015)
Hepatotoxicity	Hepatotoxicity is predicted if a compound has previous history of adverse effect to the liver.	YES or NO	(Pires et al., 2015)

Table 2. Molecular docking scores of FLT3 inhibitors.

S/N			Compound name	PubChem ID	Binding energy (kcal/mol)	Sources
1.			Glabridin	124052	−10.2	Licorice (Root extract), Glycyrrhiza glabra (Fabaceae)
2.			Elliptinium	42723	−10	Species in the family Apocynaceae, for example, Bleekeria vitensis
3.			Ellipticine	3213	−9.9	Genera Ochrosia, Rauvolfia, Aspidosperma, and Apocynaceae
4.			Mezerein	24832075	−9.9	Daphne mezereum (Thymelaeaceae) and related plants
5.			Ursolic acid	64945	−9.9	Peels of fruits, herbs and spices, for example, Apple, Malus domestica
6.			Formononetin	5287969	−9.7	Red clover, green beans, lima beans, soy
7.			Cycloartocarpesin	15224382	−9.6	Genera Artocarpus e.g. Artocarpus heterophyllus (Jackfruit)
8.			Hypericin	3663	−9.6	Genera Hypericum (Saint John's wort).
9.			Silymarin	5213	−9.6	Seeds of milk thistle Silybum marianum (L.)
10.			Indirubin	10177	−9.5	Indigo naturalis, Indigofera tinctoria, Strobilanthes cusia
11.			Pomiferin	4871	−9.5	Maclura pomifera (Osage Orange) (Moraceae)
12.			Naringin	442428	−9.4	Citrus fruits, especially in grapefruit
13.			Amooranin	11503749	−9.3	Stem bark of the tropical tree Amoora rohituka
14.			Matteucinol	160490	−9.3	Miconia chamissois (Melastomataceae)
15.			Vitexin	5280441	−9.3	Leaves of Phyllostachys nigra (Bamboo), passion flower, Pearl millet
16.			9-methoxyellipticine	72512	−9.2	Roots of Ochrosia acuminate (Apocynaceae)
17.			Sophoraflavanone B	509245	−9.2	Roots of Desmodium caudatum
18.			Withanolide	53477765	−9.2	Nightshade plant family, for example, Datura, Solanum, Withania, Jaborosa
19.			Baicalin	64982	−9.2	Plants in Genus Scutellaria and in Oroxylum indicum
Standard FLT3 drugs						Target
1.		Sorafenib		216239	−9	Fms-like tyrosine kinase 3 (FLT3) inhibitor
2.		Gilteritinib		49803313	−8.5	Fms-like tyrosine kinase 3 (FLT3) inhibitor
Other top performing anticancer drugs
3.	Sonidegib			24775005	−10.2	SMO inhibitor
4.	Venetoclax			49846579	−10	Bcl-2 inhibitor
5.	Daurismo/Glasdegib			25166913	−9.4	SMO inhibitor

Figure 1. The 3D and 2D structures of gilteritinib in complex with FLT3 (PDB ID: 6JQR) before docking.

Figure 2. The 3D and 2D structures of glabridin, cycloartocarpesin, sorafenib and gilteritinib complexes.

Figure 3. Selected 2D structural complexes of front-runners.

Figure 4. The 2D structures of top performing ligands and standard inhibitors of FLT3.

Table 3. Physicochemical and druglikeness properties of FLT3 inhibitors by SwissADME.

S/N	Compound name	Physicochemical Properties							Lipophilicity	Water solubility	Druglikeness
		MW	nHA	HBA	HBD	MR	TPSA	RB	Log PO/W	Log S	Lipinski’s rule of 5
1.	Glabridin	324.37	24	4	1	93.25	58.92	1	3.89	−4.61	Yes; 0 violation
2.	Elliptinium	277.34	21	1	2	88.86	39.90	0	3.62	−5.04	Yes; 0 violation
3.	Ellipticine	246.31	19	1	1	81.04	28.68	0	4.49	−5.05	Yes; 0 violation
4.	Mezerein	654.70	48	10	3	171.63	144.28	8	2.91	−5.96	Yes; 1 vio: MW > 500
5.	Ursolic acid	456.70	33	3	2	136.91	57.53	1	7.09	−7.23	Yes; 1 viol.: MLOGP > 4.15
6.	Formononetin	268.26	20	4	1	76.43	59.67	2	3.17	−3.73	Yes; 0 violation
7.	Cycloartocarpesin	352.24	26	6	3	98.11	100.13	1	3.65	−4.68	Yes; 0 violation
8.	Hypericin	504.44	38	8	6	144.52	155.52	0	5.79	−6.99	No; 2 vio: MW > 500, NHorOH > 5
9.	Silymarin	482.44	35	10	5	120.55	155.14	4	1.71	−4.14	Yes; 0 violation
10.	Indirubin	262.26	20	3	2	80.62	65.45	1	2.81	−3.67	Yes; 0 violation
11.	Pomiferin	420.45	31	6	3	121.83	100.13	3	5.16	−6.11	Yes; 0 violation
12.	Naringin	580.53	41	14	8	134.91	225.06	6	−1.49	−2.98	No; 3 violations: MW > 500, NorO > 10, NHorOH > 5
13.	Amooranin	470.68	34	4	2	136.85	74.60	2	6.41	−6.37	Yes; 1 violation: MLOGP > 4.15
14.	Matteucinol	314.33	23	5	2	85.97	75.99	2	3.11	−4.22	Yes; 0 violation
15.	Vitexin	432.38	31	10	7	106.61	181.05	3	−0.23	−2.84	Yes; 1 violation: NHorOH > 5
16.	9-methoxyellipticine	276.33	21	2	1	87.53	37.91	1	4.49	−5.09	Yes; 0 violation
17.	Sophoraflavanone B	340.37	25	5	3	95.29	86.99	3	3.69	−4.91	Yes; 0 violation
18.	Withanolide	470.60	34	6	2	127.53	96.36	2	3.50	−4.59	Yes; 0 violation
19.	Baicalin	446.36	32	11	6	106.72	187.12	4	0.14	−3.41	No; 2 viols: NorO > 10, NHorOH > 5
Standard FLT3 drugs
Sorafenib		464.82	32	7	3	112.48	92.35	9	6.32	−5.11	Yes; 0 violation
Gilteritinib		552.71	40	11	3	168.43	121.11	9	1.36	−5.08	No; 2 viols: MW > 500, NorO > 10
Other top performing anticancer drugs
Sonidegib		485.50	35	7	1	130.88	63.69	7	6.51	−6.43	Yes; 0 violation
Venetoclax		868.44	61	11	3	246.70	183.09	14	8.79	−9.78	No; 2 viols: MW > 500, NorO > 10
Daurismo/ glasdegib		374.44	28	4	3	111.53	96.84	5	2.50	−3.72	Yes; 0 violation

Abbreviations: MW = Molecular weight (Dalton); nHA = Number of heavy atoms; HBA = Number of hydrogen bond acceptors; HBD = Number of hydrogen bond donors; MR = Molecular refractivity; TPSA = Topological polar surface area (Ų); RB = Number of rotatable bonds.

Table 4. ADMET properties of FLT3 inhibitors by pkCMS.

S/N	Compound name	Absorption			Distribution		Metabolism		Excretion	Toxicity
		Caco-2	Int. abs	P-gp	BBB	CNS	CYP2D6	CYP3A4	TC	Ames	MRTD	LD50	Htox
1.	Glabridin	1.284	94.16	I	0.087	−1.8	No	Yes	0.121	No	−0.395	2.523	No
2.	Elliptinium	1.407	95.204	II	0.56	−1.407	Yes	Yes	1.02	Yes	0.53	2.32	No
3.	Ellipticine	1.407	95.756	–	0.414	−1.209	No	Yes	0.535	Yes	0.288	2.236	No
4.	Mezerein	0.68	100	I&II	−1.074	−3.287	No	Yes	0.143	No	0.03	2.725	No
5.	Ursolic acid	1.171	100	−	−0.141	−1.187	No	Yes	0.083	No	0.199	2.054	Yes
6.	Formononetin	1.253	96.112	−	0.157	−1.993	No	Yes	0.258	No	0.008	1.946	No
7.	Cycloartocarpesin	0.87	89.563	II	−1.094	−2.074	No	Yes	0.549	No	0.301	2.421	No
8.	Hypericin	−2.735	100	I&II	−1.561	−3.443	No	Yes	0.004	No	0.438	2.482	No
9.	Silymarin	0.435	61.861	I&II	−1.207	−3.639	No	No	−0.103	No	0.65	2.559	No
10.	Indirubin	0.805	91.285	–	0.022	−1.84	No	Yes	0.339	No	−0.428	2.373	No
11.	Pomiferin	0.655	96.598	I&II	−1.159	−1.831	No	Yes	0.11	No	0.232	2.452	No
12.	Naringin	−0.658	25.796	–	−1.6	−4.773	No	No	0.318	No	0.43	2.495	No
13.	Amooranin	0.473	100	–	0.111	−1.473	No	Yes	−0.054	No	0.208	2.453	No
14.	Matteucinol	1.188	91.428	–	−0.075	−2.01	No	Yes	0.133	No	−0.457	2.183	No
15.	Vitexin	−0.956	46.695	–	−1.449	−3.834	No	No	0.444	No	0.577	2.595	No
16.	9-methoxyellipticine	1.547	95.422	II	0.381	−1.255	No	Yes	0.534	Yes	0.338	2.225	Yes
17.	Sophoraflavanone B	1.304	91	–	−0.925	−2.13	No	Yes	0.119	No	−0.246	1.957	No
18.	Withanolide	0.831	99.2	I&II	−0.315	−2.696	No	Yes	0.347	No	−0.867	2.831	No
19.	Baicalin	−0.67	26.224	−	−1.331	−3.811	No	No	0.04	No	0.652	2.634	No
Standard FLT3 drugs
Sorafenib		0.762	85.494	I&II	−1.473	−2.025	No	Yes	−0.213	No	0.253	2.14	Yes
Gilteritinib		0.738	64.97	I	−1.14	−3.232	No	Yes	0.904	No	−0.112	2.429	Yes
Other top performing anticancer drugs
Sonidegib		1.222	93.132	I&II	−0.084	−1.876	No	Yes	−0.063	No	−0.132	2.666	Yes
Venetoclax		0.847	100	I&II	−1.747	−3.119	No	Yes	−0.096	No	0.278	2.604	Yes
Daurismo/glasdegib		0.471	84.058	I&II	−1.025	−2.279	No	Yes	0.722	Yes	0.373	2.539	Yes

Abbreviations: Caco-2 permeability (log Papp in 10-6 cm/s); Int. abs = Intestinal absorption (% Absorbed); P-gp = P-glycoprotein inhibitors I or II; BBB permeability = Blood-brain barrier permeability (log BB); CNS permeability = Central nervous system permeability (log PS); TC = Total clearance (log ml/min/kg); MRTD = Maximum tolerated dose (human) (log mg/kg/day); LD50 = Lethal Dose at 50% Inhibition (Oral Rat Acute Toxicity (mol/kg)).

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