Identification of structural fingerprints among natural inhibitors of HDAC1 to accelerate nature-inspired drug discovery in cancer epigenetics.

Histone deacetylase 1 (HDAC1), a class I HDAC enzyme, is crucial for histone modification. Currently, it is emerged as one of the important biological targets for designing small molecule drugs through cancer epigenetics. Along with synthetic inhibitors different natural inhibitors are showing potential HDAC1 inhibitions. In order to gain insights into the relationship between the molecular structures of the natural inhibitors and HDAC1, different molecular modelling techniques (Bayesian classification, recursive partitioning, molecular docking and molecular dynamics simulations) have been applied on a dataset of 155 HDAC1 nature-inspired inhibitors with diverse scaffolds. The Bayesian study showed acceptable ROC values for both the training set and test sets. The Recursive partitioning study produced decision tree 1 with 6 leaves. Further, molecular docking study was processed for generating the protein ligand complex which identified some potential amino acid residues such as F205, H28, L271, P29, F150, Y204 for the binding interactions in case of natural inhibitors. Stability of these HDAC1-natutal inhibitors complexes has been also evaluated by molecular dynamics simulation study. The current modelling study is an attempt to get a deep insight into the different important structural fingerprints among different natural compounds modulating HDAC1 inhibition.Communicated by Ramaswamy H. Sarma.

Unveiling critical structural features for effective HDAC8 inhibition: a comprehensive study using quantitative read-across structure-activity relationship (q-RASAR) and pharmacophore modeling.

Histone deacetylases constitute a group of enzymes that participate in several biological processes. Notably, inhibiting HDAC8 has become a therapeutic strategy for various diseases. The current inhibitors for HDAC8 lack selectivity and target multiple HDACs. Consequently, there is a growing recognition of the need for selective HDAC8 inhibitors to enhance the effectiveness of therapeutic interventions. In our current study, we have utilized a multi-faceted approach, including Quantitative Structure-Activity Relationship (QSAR) combined with Quantitative Read-Across Structure-Activity Relationship (q-RASAR) modeling, pharmacophore mapping, molecular docking, and molecular dynamics (MD) simulations. The developed q-RASAR model has a high statistical significance and predictive ability (Q2F1:0.778, Q2F2:0.775). The contributions of important descriptors are discussed in detail to gain insight into the crucial structural features in HDAC8 inhibition. The best pharmacophore hypothesis exhibits a high regression coefficient (0.969) and a low root mean square deviation (0.944), highlighting the importance of correctly orienting hydrogen bond acceptor (HBA), ring aromatic (RA), and zinc-binding group (ZBG) features in designing potent HDAC8 inhibitors. To confirm the results of q-RASAR and pharmacophore mapping, molecular docking analysis of the five potent compounds (44, 54, 82, 102, and 118) was performed to gain further insights into these structural features crucial for interaction with the HDAC8 enzyme. Lastly, MD simulation studies of the most active compound (54, mapped correctly with the pharmacophore hypothesis) and the least active compound (34, mapped poorly with the pharmacophore hypothesis) were carried out to validate the observations of the studies above. This study not only refines our understanding of essential structural features for HDAC8 inhibition but also provides a robust framework for the rational design of novel selective HDAC8 inhibitors which may offer insights to medicinal chemists and researchers engaged in the development of HDAC8-targeted therapeutics.

Unraveling HDAC11: Epigenetic orchestra in different diseases and structural insights for inhibitor design.

Histone deacetylase 11 (HDAC11), a member of the HDAC family, has emerged as a critical regulator in numerous physiological as well as pathological processes. Due to its diverse roles, HDAC11 has been a focal point of research in recent times. Different non-selective inhibitors are already approved, and research is going on to find selective HDAC11 inhibitors. The objective of this review is to comprehensively explore the role of HDAC11 as a pivotal regulator in a multitude of physiological and pathological processes. It aims to delve into the intricate details of HDAC11's structural and functional aspects, elucidating its molecular interactions and implications in different disease contexts. With a primary focus on elucidating the structure-activity relationships (SARs) of HDAC11 inhibitors, this review also aims to provide a holistic understanding of how its molecular architecture influences its inhibition. Additionally, by integrating both established knowledge and recent research, the review seeks to contribute novel insights into the potential therapeutic applications of HDAC11 inhibitors. Overall, the scope of this review spans from fundamental research elucidating the complexities of HDAC11 biology to the potential of targeting HDAC11 in therapeutic interventions.

Density functional theory (DFT) studies in HDAC-based chemotherapeutics: Current findings, case studies and future perspectives.

Density Functional Theory (DFT) is a quantum chemical computational method used to predict and analyze the electronic properties of atoms, molecules, and solids based on the density of electrons rather than wavefunctions. It provides insights into the structure, bonding, and behavior of different molecules, including those involved in the development of chemotherapeutic agents, such as histone deacetylase inhibitors (HDACis). HDACs are a wide group of metalloenzymes that facilitate the removal of acetyl groups from acetyl-lysine residues situated in the N-terminal tail of histones. Abnormal HDAC recruitment has been linked to several human diseases, especially cancer. Therefore, it has been recognized as a prospective target for accelerating the development of anticancer therapies. Researchers have studied HDACs and its inhibitors extensively using a combination of experimental methods and diverse in-silico approaches such as machine learning and quantitative structure-activity relationship (QSAR) methods, molecular docking, molecular dynamics, pharmacophore mapping, and more. In this context, DFT studies can make significant contribution by shedding light on the molecular properties, interactions, reaction pathways, transition states, reactivity and mechanisms involved in the development of HDACis. This review attempted to elucidate the scope in which DFT methodologies may be used to enhance our comprehension of the molecular aspects of HDAC inhibitors, aiding in the rational design and optimization of these compounds for therapeutic applications in cancer and other ailments. The insights gained can guide experimental efforts toward developing more potent and selective HDAC inhibitors.

Advances in structure-activity relationships of HDAC inhibitors as HIV latency-reversing agents.

INTRODUCTION: HIV-infected cells may rebound due to the existence of the silent HIV-infected memory CD4+ T cells (HIV latency). This HIV latency makes the disease almost incurable. In latency, the integrated proviral DNA of HIV is transcriptionally silenced partly due to the activity of histone deacetylases (HDACs). Hence, inhibition of HDAC is considered a prime target for HIV latency reversal. AREAS COVERED: A brief biology and function of HDACs have been discussed to identify key points to design HDAC inhibitors (HDACis). This article summarizes recent achievements in the development of HDACis to achieve HIV latency reversal. Structure-activity relationships (SARs) of some series of compounds were also explored. EXPERT OPINION: Depletion of the HIV reservoir is the only way to end this deadly epidemic. HDACis are latency-reversing agents (LRA) that can be used to 'shock' the latently infected CD4+ T cells to induce them to produce viral proteins. It is interesting to note that HDAC3, which is extensively expressed in resting T cells, is specifically preferred by benzamide-containing HDACis for inhibition. Thus, the benzamide class of compounds should be explored. Nevertheless, more data on selective HDAC inhibition is needed for further development of HDACis in HIV latency reversal.

HDAC9 as a Privileged Target: Reviewing its Role in Different Diseases and Structure-activity Relationships (SARs) of its Inhibitors.

HDAC9 is a histone deacetylase enzyme belonging to the class IIa of HDACs which catalyses histone deacetylation. HDAC9 inhibit cell proliferation by repairing DNA, arresting the cell cycle, inducing apoptosis, and altering genetic expression. HDAC9 plays a significant part in human physiological system and are involved in various type of diseases like cancer, diabetes, atherosclerosis and CVD, autoimmune response, inflammatory disease, osteoporosis and liver fibrosis. This review discusses the role of HDAC9 in different diseases and structure-activity relationships (SARs) of various hydroxamate and non-hydroxamate-based inhibitors. SAR of compounds containing several scaffolds have been discussed in detail. Moreover, structural requirements regarding the various components of HDAC9 inhibitor (cap group, linker and zinc-binding group) has been highlighted in this review. Though, HDAC9 is a promising target for the treatment of a number of diseases including cancer, a very few research are available. Thus, this review may provide useful information for designing novel HDAC9 inhibitors to fight against different diseases in the future.

Are inhibitors of histone deacetylase 8 (HDAC8) effective in hematological cancers especially acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)?

Histone deacetylase 8 (HDAC8) aberrantly deacetylates histone and non-histone proteins. These include structural maintenance of chromosome 3 (SMC3) cohesin protein, retinoic acid induced 1 (RAI1), p53, etc and thus, regulating diverse processes such as leukemic stem cell (LSC) transformation and maintenance. HDAC8, one of the crucial HDACs, affects the gene silencing process in solid and hematological cancer progressions especially on acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). A specific HDAC8 inhibitor PCI-34051 showed promising results against both T-cell lymphoma and AML. Here, we summarize the role of HDAC8 in hematological malignancies, especially in AML and ALL. This article also introduces the structure/function of HDAC8 and a special attention has been paid to address the HDAC8 enzyme selectivity issue in hematological cancer especially against AML and ALL.

Recent trends in fragment-based anticancer drug design strategies against different targets: A mini-review.

Cancer is a rapidly growing disease in modern society. Chemotherapy is the first choice for cancer treatment. Design and development of new chemotherapeutic drugs by targeting specific proteins are put down by a high attrition rate at different stages. Fragment-based drug design (FBDD) is one of the successful structure-based drug design processes to avoid attrition-related problems. This review highlighted the computational and experimental FBDD techniques used to design molecules with anticancer properties. This study describes FBBD strategies for different targets like aurora kinase, phosphoinositide-dependent protein kinase-1 (PDK1), signal transducer and activator of transcription 3 (STAT3), myeloid cell leukemia-1 (Mcl-1), tankyrase (TNKS), choline kinase, protein kinase, tyrosine kinase and lysine-specific demethylase 1 (LSD1) which are vital targets for cancer treatments. This review will enrich the scientific community to understand the fragment-based design strategies for finding suitable leads over high throughput screening (HTS) in the future.

Remdesivir: Mechanism of Metabolic Conversion from Prodrug to Drug.

BACKGROUND: Remdesivir (GS-5734) has emerged as a promising drug during the challenging times of COVID-19 pandemic. Being a prodrug, it undergoes several metabolic reactions before converting to its active triphosphate metabolite. It is important to establish the atomic level details and explore the energy profile of the prodrug to drug conversion process. METHODS: In this work, Density Functional Theory (DFT) calculations were performed to explore the entire metabolic path. Further, the potential energy surface (PES) diagram for the conversion of prodrug remdesivir to its active metabolite was established. The role of catalytic triad of Hint1 phosphoramidase enzyme in P-N bond hydrolysis was also studied on a model system using combined molecular docking and quantum mechanics approach. RESULTS: The overall energy of reaction is 11.47 kcal/mol exergonic and the reaction proceeds through many steps requiring high activation energies. In the absence of a catalyst, the P-N bond breaking step requires 41.78 kcal/mol, which is reduced to 14.26 kcal/mol in a catalytic environment. CONCLUSION: The metabolic pathways of model system of remdesivir (MSR) were explored completely and potential energy surface diagrams at two levels of theory, B3LYP/6-311++G(d, p) and B3LYP/6-31+G(d), were established and compared. The results highlight the importance of an additional water molecule in the metabolic reaction. The PN bond cleavage step of the metabolic process requires the presence of an enzymatic environment.

Imidazopyridine, a promising scaffold with potential medicinal applications and structural activity relationship (SAR): recent advances.

Imidazopyridine scaffold has gained tremendous importance over the past few decades. Imidazopyridines have been expeditiously used for the rationale design and development of novel synthetic analogs for various therapeutic disorders. A wide variety of imidazopyridine derivatives have been developed as potential anti-cancer, anti-diabetic, anti-tubercular, anti-microbial, anti-viral, anti-inflammatory, central nervous system (CNS) agents besides other chemotherapeutic agents. Imidazopyridine heterocyclic system acts as a key pharmacophore motif for the identification and optimization of lead structures to increase medicinal chemistry toolbox. The present review highlights the medicinal significances of imidazopyridines for their rationale development as lead molecules with improved therapeutic efficacies. This review further emphasis on the structure-activity relationships (SARs) of the various designed imidazopyridines to establish a relationship between the key structural features versus the biological activities.Communicated by Ramaswamy H. Sarma.

Reactive Metabolites from Thiazole-Containing Drugs: Quantum Chemical Insights into Biotransformation and Toxicity.

Drugs containing thiazole and aminothiazole groups are known to generate reactive metabolites (RMs) catalyzed by cytochrome P450s (CYPs). These RMs can covalently modify essential cellular macromolecules and lead to toxicity and induce idiosyncratic adverse drug reactions. Molecular docking and quantum chemical hybrid DFT study were carried out to explore the molecular mechanisms involved in the biotransformation of thiazole (TZ) and aminothiazole (ATZ) groups leading to RM epoxide, S-oxide, N-oxide, and oxaziridine. The energy barrier required for the epoxidation is 13.63 kcal/mol, that is lower than that of S-oxidation, N-oxidation, and oxaziridine formation (14.56, 17.90, and 20.20, kcal/mol respectively). The presence of the amino group in ATZ further facilitates all the metabolic pathways, for example, the barrier for the epoxidation reaction is reduced by ∼2.5 kcal/mol. Some of the RMs/their isomers are highly electrophilic and tend to form covalent bonds with nucleophilic amino acids, finally leading to the formation of metabolic intermediate complexes (MICs). The energy profiles of these competitive pathways have also been explored.

Characterization of interactions between cromolyn sodium and bovine serum albumin by spectroscopic, calorimetric and computational methods.

Cromolyn sodium (CS), an anti-inflammatory drug is used in the treatment of allergic disorders. Bovine serum albumin (BSA) a blood plasma protein is used as a model protein for studying protein folding and ligand binding mechanism as it is the main transporter protein which decides the disposition and pharmacodynamics of numerous drugs. In this study, interaction of CS with BSA was investigated using isothermal titration calorimetry, UV-vis, fluorescence, circular dichroism (CD) spectroscopy and molecular docking techniques. Steady state fluorescence data revealed that BSA-CS complex formation occurred through static mode of quenching. Negative values of Gibbs free energy change and enthalpy change showed that BSA-CS complexation was spontaneously favorable and enthalpy driven. CS preferentially interacted at Sudlow's site I (sub-domain IIA) of BSA and the finding was further substantiated by molecular docking study. The binding of CS induced changes in secondary motif of BSA resulting decrease of α-helical content as evident from CD. We explored detailed thermodynamic and structural parameters of interaction of CS to BSA that will be helpful for understanding the more precise binding mechanism of the drug at molecular level.Communicated by Ramaswamy H. Sarma.