An in silico drug repurposing approach to identify HDAC1 inhibitors against glioblastoma

Figures & data

Table 1. List of drugs from the ZINC15 database with docking score and binding energy scores.

Sl. No.	ZINC ID	Drugs	Dock Score (XP) (Kcal/mol)	ΔGBind Prime-MMGBSA (Kcal/mol)
1.	ZINC22010649	Panobinostat	−10.558	−41.96
2.	ZINC121541	Mebendazole	−10.531	−35.87
3.	ZINC3818726	Belinostat	−10.020	−35.28
4.	ZINC1673	Melphalan	−9.032	−27.53
5.	ZINC4392649	Tasimelteon	−8.440	−25.68
6.	ZINC1530886	Telmisartan	−8.386	−51.75
7.	ZINC2272	Ketoprofen	−8.122	−36.10
8.	ZINC1550477	Lapatinib	−7.999	−59.20
9.	ZINC403079	Midodrine	−7.809	−29.52
10.	ZINC4097427	Candesartan	−7.305	−50.86

Table 2. Ligand interaction diagram of the selected ten drugs after XP docking.

Sl. No.	Drugs	Ligand interaction diagram	Bonding interaction	Non-bonding interaction
1.	ZINC22010649 (Panobinostat)		H bond: HIS140, GLY301, GLY149, ASP99, PRO206 Salt Bridge: ASP99 Pi-Pi Stacking: PHE150, PHE205	Polar: HIS141, HIS178 Hydrophobic: LEU139, MET30, LEU271, TYR204, PHE205, PRO206, CYS151, PHE150, TYR303 Charged Negative: GLU203, ASP264, ASP176, ASP99
2.	ZINC121541 (Mebendazole)		H bond: GLY149 Pi-Pi Stacking: HIS178, PHE205, PHE150	Hydrophobic: TYR303, PHE205, TYR204, PRO29, LEU271, PHE150, CYS151, LEU139 Charged Negative: ASP264, ASP176 Polar: HIS178, GLN260, HIS141, HIS140
3.	ZINC3818726 (Belinostat)		H bond: HIS140, GLY149 Pi- Pi Stacking: HIS178	Hydrophobic: TYR303, LEU271, PRO206, PHE205, PHE150, CYS151, LEU139 Charged Negative: ASP264, ASP176, ASP99 Polar: HIS178, HIS141, HIS140, SER148
4.	ZINC1673 (Melphalan)		H bond: GLY139, TYR303 Salt Bridge: ASP264 Pi-Pi Stacking: HIS178	Hydrophobic: PRO29, MET30, TYR303, PHE150, CYS151, PHE205, TYR204, LEU271 Charged Negative: ASP99, ASP264, ASP176 Polar: HIS178, HIS141, HIS140
5.	ZINC4392649 (Tasimelteon)		H bond: TYR303, HIS141 Pi-Pi Stacking: HIS141	Hydrophobic: TYR303, CYS151, PHE150, LEU271, LEU139, MET30, PHE205, PRO206 Charged Negative: ASP264, ASP99, ASP176, ASP181 Polar: SER148, GLN260, HIS140, HIS141, HIS178
6.	ZINC1530886 (Telmisartan)		H bond: ASP99, GLU230 Salt Bridge: ASP99, ASP230 Pi-Pi Stacking: TYR204, PHE150, HIS178 Pi-Pi Cation: PHE205, PHE150	Hydrophobic: MET350, TYR204, PHE205, PHE150, TYR303, LEU271, CYS273 Charged Positive: ARG270 Charged Negative: ASP230, GLU203, ASP99 Polar: HIS178, HIS141
7.	ZINC2272 (Ketoprofen)		H bond: HIS178, ASP99 Salt Bridge: ASP99 Pi-Pi Cation: PHE205, PHE150	Hydrophobic: LEU271, TYR204, PHE205, PHE150 Charged Negative: GLU203, ASP99 Polar: HIS178, HIS141
8.	ZINC1550477 (Lapatinib)		H bond: TYR303, ASP99 Salt Bridge: ASP99 Pi-Pi Stacking: TYR303, TYR204	Hydrophobic: PHE109, MET30, PRO29, TYR303, LEU271, TYR204, PHE205, ALA147, PHE150, CYS151, LEU139 Charged Positive: ARG34 Charged Negative: ASP99, ASP146 Polar: HIS178, HIS140, HIS141, SER148, ASN95
9.	ZINC403079 (Midodrine)		H bond: HIS178, GLY149 Salt Bridge: ASP176 Metal: Zn600	Hydrophobic: TYR204, PHE205, LEU271, MET30, TYR303, LEU139, PHE150, CYS151 Charged Negative: ASP264, ASP176 and ASP99 Polar: HIS140, HIS141 and GLN260
10.	ZINC4097427 (Candesartan)		H bond: HIS178, ASP99 Salt Bridge: ASP99 Pi-Pi Stacking: HIS178 Pi-Pi Cation: PHE205	Hydrophobic: CYS273, LEU271, TYR303, PHE150, PHE205, TYR204 Charged Positive: ARG270 Charged Negative: ASP99, GLU203 Polar: HIS178

Table 3. Predicted ADME properties of the selected drugs using the SwissADME tool.

Compound	Molecular weight	Log P	HB Donor	HB Acceptor	PSA	Rule of five	BBB Permeability	GI absorption
Panobinostat	349.43	2.98	4	3	77.15	0	Yes	High
Mebendazole	295.29	2.53	2	4	87.31	0	No	High
Belinostat	318.35	1.47	3	4	103.88	0	No	High
Melphalan	305.20	1.33	2	3	66.56	0	Yes	High
Tasimelteon	245.32	2.50	1	2	38.33	0	Yes	High
Telmisartan	514.62	5.92	1	4	72.94	2	No	Low
Ketoprofen	254.28	2.85	1	3	54.37	0	Yes	High
Lapatinib	581.06	5.13	2	8	114.73	2	No	Low
Midodrine	254.28	0.18	3	5	93.81	0	No	High
Candesartan	610.66	5.46	1	10	143.34	3	No	Low

Log P—Partition coefficient; HB—Hydrogen bond; PSA—Polar Surface Area; BBB—Blood–brain barrier; GI—Gastrointestinal.

Figure 1. RMSD plot of ligand-protein complexes. RMSD of (a) Panobinostat (b) Tasimelteon and (c) Melphalan and (d) Ketoprofen with the active site of HDAC1 protein.

Figure 2. MMGBSA of drug ligand complexes.

Figure 3. Ligand-Protein interaction diagram after MD of (a) Panobinostat (b) Tasimelteon and (c) Melphalan and (d) Ketoprofen with the HDAC1 protein.

Figure 4. Ligand-protein contacts of (a) Panobinostat (b) Tasimelteon (c) Melphalan and (d) Ketoprofen throughout 100 ns time frame with HDAC1 protein.

Figure 5. Concentration vs Percentage cell death graph of (a) Panobinostat (b) Melphalan (c) Tasimelteon (d) Temozolomide in U87 MG cells.

Figure 6. Concentration vs Percentage cell death graph of (a) Panobinostat (b) Melphalan (c) Tasimelteon (d) Temozolomide in C6 glial cells.

Figure 7. Representative image of western blot analysis of HDAC1 protein in U87 MG cells and relative density ratio of HDAC1/α-tubulin. The values are represented as mean ± SEM, where *p < 0.01 vs control group (n = 3). 10 and 30 represent the IC₁₀ and IC₃₀ doses of M–Melphalan, T–Tasimelteon, P–Panobinostat and TM–Temozolomide, respectively.

Figure 8. Representative image of western blot analysis of HDAC1 protein in C6 glial cells and relative density ratio of HDAC1/α-tubulin. The values are represented as mean ± SEM, where *p < 0.01 vs control group (n = 3). 10 and 30 represent the IC₁₀ and IC₃₀ doses of M- Melphalan, T- Tasimelteon, P- Panobinostat and TM- Temozolomide, respectively.