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Molecular docking and ADMET analysis of hydroxamic acids as HDAC2 inhibitors.

ABSTRACT: Histone deacetylase (HDAC2) belongs to the hydrolase family and a promising target for cancers. We reported 96 hydroxamic compounds optimized using hydrogen-donors, hydrophobic and electron withdrawing groups followed by molecular docking studies. The optimized compounds show good LibDock score and H-bond interaction in the active site of HDAC2. We selected 20 compounds as the best HDAC2 inhibitors based on the LibDock score, binding energy and hydrogen bonding. ADMET predictions on these compounds show good absorption, BBB penetration and no liver toxicity. We subsequently report four compounds selected as best HDAC2 inhibitors based on the LibDock, binding energy, H-bonding and ADMET properties.

SUBMITTER: Alsawalha M

PROVIDER: S-EPMC6614126 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Molecular docking and ADMET analysis of hydroxamic acids as HDAC2 inhibitors.

Alsawalha Murad M Rao Bolla Srinivasa S Kandakatla Naresh N Srinivasadesikan Venkatesan V Veeraraghavan Vishnu Priya VP Surapaneni Krishna Mohan KM

Bioinformation 20190530 6

Histone deacetylase (HDAC2) belongs to the hydrolase family and a promising target for cancers. We reported 96 hydroxamic compounds optimized using hydrogen-donors, hydrophobic and electron withdrawing groups followed by molecular docking studies. The optimized compounds show good LibDock score and H-bond interaction in the active site of HDAC2. We selected 20 compounds as the best HDAC2 inhibitors based on the LibDock score, binding energy and hydrogen bonding. ADMET predictions on these compou ...[more]

PMID: 31312074

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Project description:BackgroundPreservatives have to be added in food, pharmaceuticals and cosmetics products to maintain their shelf life. However, the existing chemical based preservatives have been associated with severe side effects that compel the researchers to find better safe preservatives based on natural products. G-6-P synthase is an important enzyme for bacterial and fungal cell wall synthesis and offers as a potential target to find better G-6-P synthase inhibitors based antimicrobial compounds. Naringenin, a flavanone, has been reported for a wide range of pharmacological activities including antimicrobial activity, which makes it a potential candidate to be explored as novel G-6-P synthase inhibitor.ResultsThe synthesis of naringenin derivatives with potent G-6-P synthase inhibitor having remarkable antioxidant, antimicrobial and preservative efficacy was performed. Among the synthesized compounds, the compound 1 possessed good antioxidant activity (IC50 value, 6.864 ± 0.020 µM) as compared to standard ascorbic acid (IC50 value, 8.110 ± 0.069 µM). The antimicrobial activity of synthesized compounds revealed compound 1 as the most potent compound (pMIC 1.79, 1.79, 1.49, 1.49, 1.49 and 1.49 μM/mL for P. mirabilis, P. aeruginosa, S. aureus, E. coli, C. albicans and A. niger respectively) as compared to standard drugs taken. The compound 2 showed comparable activity against P. mirabilis (pMIC 1.14 μM/mL), C. albicans (pMIC 1.14 μM/mL) while the compound 3 also showed comparable activity against C. albicans (pMIC 1.16 μM/mL) as well A. niger (pMIC 1.46 μM/mL), likewise the compound 4 showed comparable activity against P. mirabilis (pMIC 1.18 μM/mL) as compared to the standard drugs streptomycin (pMIC 1.06, 1.36, 1.06 and 1.96 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively), ciprofloxacin (pMIC 1.12, 1.42, 1.12 and 1.42 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively), ampicillin (pMIC 1.14, 0.84, 0.84 and 1.74 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively) and fluconazole (pMIC 1.08 and 1.38 μM/mL for C. albicans and A. niger respectively). The molecular docking with the target G-6-P synthase pdb id 1moq resulted with an better dock score for compound 1 (- 7.42) as compared to standard antimicrobial drugs, ciprofloxacin (- 5.185), ampicillin (- 5.065) and fluconazole (- 5.129) that supported the wet lab results. The preservative efficacy test for compound 1 in White Lotion USP showed the log CFU/mL value within the prescribed limit and results were comparable to standard sodium benzoate, ethyl paraben and propyl paraben as per USP standard protocol.ConclusionsThe synthesized naringenin derivatives exhibited significant G-6-P synthase inhibitory potential with good selectivity towards the selected target G-6-P synthase. Compound 1, bearing nitro group showed good antioxidant, antimicrobial and preservative efficacy compared with the standard drugs taken. The mechanistic insight about the compounds within the active site was completed by molecular docking that supported the results for novel synthesized G-6-P synthase inhibitors.

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Molecular docking and ADMET analysis of hydroxamic acids as HDAC2 inhibitors.

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Molecular docking and ADMET analysis of hydroxamic acids as HDAC2 inhibitors.

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