Design and in silico screening of aryl allyl mercaptan analogs as potential histone deacetylases (HDAC) inhibitors

Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R2 = 0.958) and a satisfactory predictive power (Q2 = 0.822; Q2F3 = 0.894). The model was validated (r2ext_ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner–Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity.

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In silico profiling of histone deacetylase inhibitory activity of compounds isolated from Cajanus cajan

Beni-Suef University Journal of Basic and Applied Sciences ◽

10.1186/s43088-021-00191-y ◽

2022 ◽

Vol 11 (1) ◽

Author(s):

Kayode Adewole ◽

Adebayo Ishola ◽

Ige Olaoye

Keyword(s):

Betulinic Acid ◽

Hdac Inhibitor ◽

In Silico ◽

Histone Deacetylases ◽

Cajanus Cajan ◽

Molecular Mechanisms ◽

Hdac Inhibitors ◽

High Morbidity ◽

Discovery Studio ◽

Potential Inhibitors

Abstract Background Cancer is responsible for high morbidity and mortality globally. Because the overexpression of histone deacetylases (HDACs) is one of the molecular mechanisms associated with the development and progression of some diseases such as cancer, studies are now considering inhibition of HDAC as a strategy for the treatment of cancer. In this study, a receptor-based in silico screening was exploited to identify potential HDAC inhibitors among the compounds isolated from Cajanus cajan, since reports have earlier confirmed the antiproliferative properties of compounds isolated from this plant. Results Cajanus cajan-derived phytochemicals were docked with selected HDACs, with givinostat as the reference HDAC inhibitor, using AutodockVina and Discovery Studio Visualizer, BIOVIA, 2020. Furthermore, absorption, distribution, metabolism and excretion (ADME) drug-likeness analysis was done using the Swiss online ADME web tool. From the results obtained, 4 compounds; betulinic acid, genistin, orientin and vitexin, were identified as potential inhibitors of the selected HDACs, while only 3 compounds (betulinic acid, genistin and vitexin) passed the filter of drug-likeness. The molecular dynamic result revealed the best level of flexibility on HDAC1 and HDAC3 compared to the wild-type HDACs and moderate flexibility of HDAC7 and HDAC8. Conclusions The results of molecular docking, pharmacokinetics and molecular dynamics revealed that betulinic acid might be a suitable HDAC inhibitor worthy of further investigation in order to be used for regulating conditions associated with overexpression of HDACs. This knowledge can be used to guide experimental investigation on Cajanus cajan-derived compounds as potential HDAC inhibitors.

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6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

Cellular Physiology and Biochemistry ◽

10.1159/000495275 ◽

2018 ◽

Vol 51 (2) ◽

pp. 543-556 ◽

Cited By ~ 4

Author(s):

Sascha Venturelli ◽

Heike Niessner ◽

Tobias Sinnberg ◽

Alexander Berger ◽

Markus Burkard ◽

...

Keyword(s):

In Silico ◽

Histone Deacetylases ◽

Histone Deacetylase Inhibitors ◽

Cellular Proliferation ◽

Hdac Inhibitors ◽

Binding Pocket ◽

Zinc Ion ◽

Melanoma Cells ◽

The Impact

Background/Aims: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). Methods: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. Results: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. Conclusion: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities.

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Identification of potential histone deacetylase inhibitory biflavonoids from Garcinia kola (Guttiferae) using in silico protein-ligand interaction

Physical Sciences Reviews ◽

10.1515/psr-2020-0099 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Kayode E. Adewole ◽

Ahmed A. Ishola ◽

Blessing O. Omolaso

Keyword(s):

In Silico ◽

Histone Deacetylases ◽

Hdac Inhibitors ◽

Intimate Relationship ◽

Binding Affinities ◽

Ligand Interaction ◽

Garcinia Kola ◽

Discovery Studio ◽

Limited Success ◽

Protein Ligand Interaction

Abstract Overactivity of histone deacetylases (HDACs) is the underlying cause of some cancers, thus, inhibiting their overactivities is a rational treatment option. However, endeavors to employ current anti-HDACs agents in cancer treatment have yielded limited success. Consequently, there is need to explore anti-HDACs natural products, especially from plants sources, because of the intimate relationship plant products and drug discovery have enjoyed over the centuries. To identify possible HDACs inhibitors, Garcinia kola (Guttiferae) seed-derived compounds were screened in silico for HDAC-inhibitory tendencies because of their reported anticancer potentials. Fifteen G. kola-derived compounds and givinostat were docked with five selected HDACs using AutodockVina, while the binding interactions of the compounds with high binding affinities for the five HDACs were viewed with Discovery Studio Visualizer BIOVIA, 2016. Results indicated that four of the compounds studied, including amentoflavone, Garcinia biflavonoid 1, Garcinia biflavonoid 2 and kolaflavanone have higher binding propensity for all the five HDACs relative to givinostat, the standard HDAC inhibitor. This study indicated that inhibition of HDAC might be another key mechanism accountable for the bioactivities of G. kola and its intrinsic compounds. The results from this study implied that the compounds could be further investigated as drugable HDAC inhibitors with potential pharmacological applications in the treatment of cancers.

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First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

10.26434/chemrxiv.12440096.v1 ◽

2020 ◽

Author(s):

Daniel Herp ◽

Johannes Ridinger ◽

Dina Robaa ◽

Stephen A. Shinsky ◽

Karin Schmidtkunz ◽

...

Keyword(s):

Histone Deacetylases ◽

High Throughput Screening ◽

Neuroblastoma Cell ◽

Hdac Inhibitors ◽

Anticancer Therapy ◽

Colony Growth ◽

Autophagic Flux ◽

Enzymatic Conversion ◽

Lysine Deacetylase

Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of the other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like spermine or spermidine. Hence, it also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin labelled acetyl spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10 mediated spermidine deacetylation in-vitro. Among those are potent inhibitors of neuroblastoma colony growth in culture that show accumulation of lysosomes, implicating disturbance of autophagic flux.

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Gold-Aptamer-Nanoconstructs Engineered to Detect Conserved Enteroviral Nucleic Acid Sequences

10.26434/chemrxiv.8312324.v1 ◽

2019 ◽

Author(s):

Veeren Chauhan ◽

Mohamed M Elsutohy ◽

C Patrick McClure ◽

Will Irving ◽

Neil Roddis ◽

...

Keyword(s):

Nucleic Acid ◽

In Silico ◽

Point Of Care ◽

Lateral Flow ◽

Nucleic Acid Sequence ◽

In Silico Screening ◽

Lateral Flow Assays ◽

Life Threatening ◽

Software And Hardware ◽

Nucleic Acid Sequences

Enteroviruses are a ubiquitous mammalian pathogen that can produce mild to life-threatening disease. Bearing this in mind, we have developed a rapid, accurate and economical point-of-care biosensor that can detect a nucleic acid sequences conserved amongst 96% of all known enteroviruses. The biosensor harnesses the physicochemical properties of gold nanoparticles and aptamers to provide colourimetric, spectroscopic and lateral flow-based identification of an exclusive enteroviral RNA sequence (23 bases), which was identified through in silico screening. Aptamers were designed to demonstrate specific complementarity towards the target enteroviral RNA to produce aggregated gold-aptamer nanoconstructs. Conserved target enteroviral nucleic acid sequence (≥ 1x10-7 M, ≥1.4×10-14 g/mL), initiates gold-aptamer-nanoconstructs disaggregation and a signal transduction mechanism, producing a colourimetric and spectroscopic blueshift (544 nm (purple) > 524 nm (red)). Furthermore, lateral-flow-assays that utilise gold-aptamer-nanoconstructs were unaffected by contaminating human genomic DNA, demonstrated rapid detection of conserved target enteroviral nucleic acid sequence (< 60 s) and could be interpreted with a bespoke software and hardware electronic interface. We anticipate our methodology will translate in-silico screening of nucleic acid databases to a tangible enteroviral desktop detector, which could be readily translated to related organisms. This will pave-the-way forward in the clinical evaluation of disease and complement existing strategies at overcoming antimicrobial resistance.

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Molecular Mechanisms of Several Novel Dipeptides with Angiotensin-Iconverting Enzyme Inhibitory Activity from In-silico Screening of Silkworm Pupae Protein

Current Pharmaceutical Biotechnology ◽

10.2174/138920101508140930153336 ◽

2014 ◽

Vol 15 (8) ◽

pp. 691-699 ◽

Cited By ~ 2

Author(s):

Wei Wang ◽

Yu Zhang ◽

Nan Wang ◽

Zuoyi Zhu

Keyword(s):

Inhibitory Activity ◽

In Silico ◽

Molecular Mechanisms ◽

In Silico Screening ◽

Silkworm Pupae

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Design and in-silico screening of Peptide Nucleic Acid (PNA) inspired novel pronucleotide scaffolds targeting COVID-19

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200923143935 ◽

2020 ◽

Vol 16 ◽

Author(s):

Bichismita Sahu ◽

Santosh Kumar Behera ◽

Rudradip Das ◽

Tanay Dalvi ◽

Arnab Chowdhury ◽

...

Keyword(s):

Nucleic Acid ◽

In Silico ◽

Peptide Nucleic Acid ◽

Large Set ◽

Nonstructural Proteins ◽

In Silico Screening ◽

Replication Process ◽

Enveloped Virus ◽

Treatment Regimens ◽

Novel Coronavirus

Introduction: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned itself into a pandemic taking a heavy toll on human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive sense single-stranded enveloped virus and quite closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced. Methods: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes nonstructural proteins like RNA dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are in the advanced stage of clinical trials including Remdesivir. While performing close investigation of the large set of nucleic acid based drugs, we were surprised to find that the synthetic nucleic acid backbone is explored very little or rare. Results: We have designed scaffolds derived from peptide nucleic acid (PNA) and subjected them for in-silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess similar binding affinity as Remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 (12,000mg/kg) as opposed to Remdesivir (LD50 =1000mg/kg). Conclusion: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid derived compounds can serve as a leading scaffold to design, synthesize and evaluate many of similar compounds for the treatment of COVID-19.

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In silico screening of pyridoxine carbamates for Anti-Alzheimer’s activities

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524920666201119144535 ◽

2020 ◽

Vol 20 ◽

Author(s):

Dnyaneshwar Baswar ◽

Abha Sharma ◽

Awanish Mishra

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

In Silico ◽

Neurodegenerative Disorder ◽

Biological Activities ◽

Cholinergic Neurons ◽

In Silico Screening ◽

In Silico Studies ◽

Bbb Permeability ◽

Ld50 Value

Background: Alzheimer’s disease (AD), an irreversible complex neurodegenerative disorder, is most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi- factorial etiology of Alzheimer’s disease, novel ligands strategy appears as up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer’s potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques. Methods: For in silico screening of physicochemical properties of compounds molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction PASS software while toxicity profile of compounds were analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6. Results: Based on in silico studies, compound 9 and 10 have been found to have better drug likeness, LD50 value, and better anti-Alzheimer’s, nootropic activities. However, these compounds had poor blood brain barrier (BBB) permeability. Compound 4 and 9 were predicted with better docking score for AChE enzyme. Conclusion: The outcome of in silico studies have suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 have shown promising drug likeness, with better safety and efficacy profile for anti-Alzheimer’s activity. However, BBB permeability appears as one the major limitation of all these compounds. Further studies are required to confirm its biological activities.

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