Novel natural inhibitors targeting B-RAF(V600E) by computational study

Figures & data

Figure 1. Molecular structure of B-RAF(V600E). (a) Initial molecular structure. (b) Surface of binding area added. Blue represents positive charge, and red represents negative charge. (c) Vemurafenib of binding area added

Table 1. Top 20 ranked compounds with higher libdock scores than Vemurafenib

Number	Compounds	Libdock score	Number	Compounds	Libdock score
1	ZINC000085541163	148.778	11	ZINC000021992902	136.566
2	ZINC000017654900	146.535	12	ZINC000028115894	136.303
3	ZINC000049784088	145.648	13	ZINC000030725991	135.633
4	ZINC000100045922	145.597	14	ZINC000029134692	135.562
5	ZINC000040866222	144.961	15	ZINC000038148193	135.145
6	ZINC000004098930	143.875	16	ZINC000000839083	135.144
7	ZINC000030731451	141.085	17	ZINC000002526389	134.996
8	ZINC000015122022	140.725	18	ZINC000028539727	134.329
9	ZINC000044352341	140.255	19	ZINC000002526388	133.941
10	ZINC000100168592	136.748	20	ZINC000038141997	133.863

Table 2. ADME (Adsorption, Distribution, Metabolism, Excretion) properties of compounds

Number	Compounds	Solubility Level^a	BBB level^b	CYP2D6^c	Hepatotoxicity^d	Absorption Level^e	PPB Level^f
1	ZINC000085541163	2	4	0	0	2	0
2	ZINC000017654900	2	4	0	1	2	0
3	ZINC000049784088	4	4	0	0	3	0
4	ZINC000100045922	0	4	0	0	3	1
5	ZINC000040866222	3	4	0	0	2	0
6	ZINC000004098930	3	4	0	1	2	0
7	ZINC000030731451	3	4	0	0	0	0
8	ZINC000015122022	2	4	1	0	2	1
9	ZINC000044352341	4	4	0	0	3	0
10	ZINC000100168592	3	4	0	0	1	1
11	ZINC000021992902	3	4	0	0	1	0
12	ZINC000028115894	0	4	0	1	3	0
13	ZINC000030725991	0	4	0	1	2	0
14	ZINC000029134692	2	1	0	0	0	1
15	ZINC000038148193	0	4	0	1	2	0
16	ZINC000000839083	2	2	0	0	0	1
17	ZINC000002526389	2	4	1	1	0	1
18	ZINC000028539727	4	4	0	1	3	0
19	ZINC000002526388	2	4	1	1	0	1
20	ZINC000038141997	1	4	0	0	3	1
21	Vemurafenib	1	4	0	1	1	1

a Aqueous-solubility level: 0 (extremely low); 1 (very low, but possible); 2 (low); 3 (good)

b Blood Brain Barrier level: 0 (Very high penetrant); 1 (High); 2 (Medium); 3 (Low); 4 (Undefined)

c Cytochrome P450 2D6 level: 0 (Non-inhibitor); 1 (Inhibitor)

d Hepatotoxicity: 0 (Nontoxic); 1 (Toxic)

e Human-intestinal absorption level: 0 (good); 1 (moderate); 2 (poor); 3 (very poor)

f Plasma Protein Binding: 0 (Absorbent weak); 1 (Absorbent strong)

Table 3. Toxicities of compounds

Number	Compounds	Mouse NTP^a		Rat NTP^a		AMES^b	DTP^c
		Female	Male	Female	Male
1	ZINC000085541163	0.4438	0.3649	0.3071	0.1583	0.0968	0.8155
2	ZINC000017654900	0.5721	0.0048	0.1620	0.5179	0.0000	0.3214
3	ZINC000049784088	0.5414	0.6126	0.2585	0.5119	0.1310	0.5735
4	ZINC000100045922	0.6084	0.5529	0.2799	0.5232	0.5603	0.5334
5	ZINC000040866222	0.5700	0.6130	0.2036	0.1981	0.1534	0.8691
6	ZINC000004098930	0.3688	0.1803	0.1948	0.3959	0.5418	0.7175
7	ZINC000030731451	0.4884	0.5856	0.2788	0.4434	0.7195	0.5720
8	ZINC000015122022	0.2996	0.5764	0.1196	0.1554	0.0002	0.8119
9	ZINC000044352341	0.4447	0.6051	0.1954	0.2056	0.2047	0.8230
10	ZINC000100168592	0.5979	0.6120	0.1388	0.2575	0.0000	0.4667
11	ZINC000021992902	0.5776	0.6142	0.2195	0.4923	0.0008	0.7642
12	ZINC000028115894	0.6187	0.7214	0.5002	0.6762	0.9884	0.7436
13	ZINC000030725991	0.5338	0.6445	0.4743	0.6484	0.9395	0.7590
14	ZINC000029134692	0.7327	0.8030	0.2570	0.5604	0.0225	0.7804
15	ZINC000038148193	0.5782	0.6239	0.4830	0.6617	0.9830	0.7408
16	ZINC000000839083	0.4011	0.5724	0.4773	0.3781	0.4972	0.4622
17	ZINC000002526389	0.3270	0.5091	0.4332	0.4770	0.0001	0.6071
18	ZINC000028539727	0.4132	0.0579	0.2043	0.2855	0.4461	0.4626
19	ZINC000002526388	0.2988	0.4387	0.4216	0.4831	0.0000	0.6178
20	ZINC000038141997	0.7046	0.6141	0.1207	0.4639	0.0000	0.4961
21	Vemurafenib	0.5128	0.6099	0.4866	0.3541	0.7223	0.5099

a < 0.3 (Non-Carcinogen); >0.7 (Carcinogen)

b < 0.3 (Non-Mutagen); >0.7 (Mutagen)

c < 0.3 (Nontoxic); >0.7 (Toxic)

Figure 2. Structures of Vemurafenib and novel compounds selected from virtual screening

Table 4. CDOCKER interaction energy of compounds with mTORC1

Compounds	CDOCKER Interaction energy (Kcal/mol)
ZINC000049784088	−64.8994
ZINC000100168592	−70.0101
Vemurafenib	−62.5375

Table 5. Hydrogen bond interaction parameters for each compound and BRAF(V600E residues

Receptor	Compound	Donor atom	Receptor Atom	Distances (Å)
BRAF(V600E)	Vemurafenib	A:CYS532:N	Molecule:N20	3.24
		A:GLN530:O	Molecule:N18	3.11
		A:LYS483:NZ	Molecule:O5	3.37
		A:GLY596:N	Molecule:O6	3.04
	ZINC000049784088	A:ASN581:OD1	ZINC000049784088:H73	2.87
		A:ASP594:OD2	ZINC000049784088:H73	2.02
		A:GLN530:O	ZINC000049784088:H57	2.23
	ZINC000100168592	A:ASP594:OD1	ZINC000100168592:H67	2.54
		A:LYS483:HZ2	ZINC000100168592:O23	2.02

Table 6. π-π interaction, π-Alkyl interaction, Alkyl interaction, π-cation interaction and Unfavorable Doner-Doner interaction, parameters for each compound and mTORC1 residues

Interaction parameters	Receptor	Compound	Donor atom	Receptor Atom	Distances (Å)
π-π interaction	BRAF(V600E)	Vemurafenib	A:TRP531	Molecule	5.87
			A:TRP531	Molecule	4.55
			A:TRP531	Molecule	5.40
			A:PHE583	Molecule	4.90
π-Alkyl interaction		Vemurafenib	A:CYS532	Molecule	4.72
			A:CYS532	Molecule	4.78
			A:ALA481	Molecule	5.10
			A:ALA481	Molecule	3.70
			A:LEU514	Molecule	5.32
			A:ALA481	Molecule	5.33
			A:LEU514	Molecule	5.48
			A:ALY483	Molecule	4.54
			A;phe595	Molecule:C1	4.82
		ZINC000049784088	A:LYS483	ZINC000049784088	4.93
			A:ILE527	ZINC000049784088	4.73
				ZINC000049784088
Alkyl interaction		Vemurafenib	A:LEU514	Molecule:C1	4.34
			A:LEU505	Molecule:C1	4.62
		ZINC000100168592	A:VAL471	ZINC000100168592:C1	4,5
π-Cation interaction		ZINC000049784088	A:LYS483:HZ3	ZINC000049784088	2.79
Unfavorable Doner-Doner interaction		Vemurafenib	A:ASP594:N	Molecule:N7	3.24

Figure 3. Schematic of intermolecular interaction of the predicted binding modes of (a) ZINC000100168592 with B-RAF(V600E), (b) ZINC000049784088 with B-RAF(V600E), and (c) Vemurafenib with B-RAF(V600E)

Figure 4. Schematic drawing of interactions between ligands and B-RAF(V600E). The surface of binding areas was added. Blue represents positive charge; red represents negative charge; and ligands are shown in sticks, with the structure around the ligand-receptor junction shown in thinner sticks. (a) ZINC000100168592-B-RAF(V600E) complex. (b) ZINC000049784088-B-RAF(V600E) complex

Figure 5. Results of molecular dynamics simulation of the compounds ZINC000100168592 and ZINC000049784088. (a) Potential energy, Average backbone root-mean-square deviation. (b) RMSD, root-mean-square deviation