Design and synthesis of pyridine-based benzamides as potent HDAC3 inhibitors as an armament against breast cancer with in vivo validation.

Some novel benzamide derivatives with modified linker group were designed and synthesized as promising HDAC3-selective inhibitors. These compounds exerted promising antiproliferative potential compared to reference molecule CI994 while tested against several cancer cell lines. Notably, all these molecules exhibited nontoxicity towards normal human cell lines.

Fosamprenavir and Tirofiban to combat COPD and cancer: A drug repurposing strategy integrating virtual screening, MD simulation, and DFT studies.

Matrix metalloproteinases (MMPs) are involved in different pathophysiological conditions like cancer, COPD, asthma, and inflammatory diseases. Among these MMPs, macrophage metalloelastase is one of the prime targets for COPD, and cancer. Therefore, to combat such diseases, potent novel macrophage metalloelastase inhibitors can be considered.

Unveiling structural components of dibenzofuran-based MMP-12 inhibitors: a comparative classification-dependent analysis with molecular docking-based virtual screening and molecular dynamics simulation.

Unlabelled: The implication of matrix metalloproteinase-12 (MMP-12) in various major disorders including cancer, COPD, cardiovascular disorders, and neurological diseases makes it a potential target for drug discovery. Contemplating the significance of MMP-12, a number of MMP-12 inhibitors were designed, synthesized and tested throughout the world but the non-selective nature of most of those molecules can lead to adverse drug interactions. In contradiction, the dibenzofuran (DBF) and dibenzothiophene (DBT) derivatives showed highly potent and selective MMP-12 inhibition.

An overview of matrix metalloproteinase-12 in multiple disease conditions, potential selective inhibitors, and drug designing strategies.

Matrix metalloproteases (MMPs) are the proteolytic enzymes accountable for extracellular matrix (ECM) modification through their Zn-dependent catalytic activity. Among these, MMP-12 is one of the crucial MMPs that contributes to various disease states including different types of cancers and other major pathophysiological conditions including COPD, asthma, emphysema, skin diseases, arthritis, vascular diseases, and neurological disorders. The majority of the MMP-12 inhibitors should have three constitutional pharmacophoric features (i.

Derivatives of D(-)-glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-III: Synthesis, biological screening and in silico binding interaction analysis.

Tyrosine kinase inhibitors (TKIs) have markedly improved the overall survival rate of patients with chronic myeloid leukemia (CML), enabling them to achieve a normal life expectancy. However, toxicity, relapse, and drug resistance continue to pose major challenges in the clinical treatment of CML. The progression of leukemia is directly connected to higher expression levels and enzymatic actions of matrix metalloproteinase-2 (MMP-2).

Exploring the key structural attributes and chemico-biological interactions of pyridinone-based SARS-CoV-2 3CL inhibitors through validated structure-based drug design strategies.

The global outbreak of COVID-19 infection is the first pandemic the world has experienced in this 21 century. The novel coronavirus 2019 (nCoV-19) also called the SARS-CoV-2 is the reason behind the severe acute respiratory syndrome (SARS) that led to this worldwide crisis. In this current post-pandemic situation, despite having effective vaccines, the paucity of orally administrable drug molecules for such infections is a major drawback in this current scenario.

Pharmacophore modeling, 3D-QSAR, and MD simulation-based overture for the discovery of new potential HDAC1 inhibitors.

Histone deacetylases (HDACs) are important epigenetic regulators that modulate the activity of histone and non-histone proteins leading to various cancers. Histone deacetylase 1 (HDAC1) is a member of class 1 HDAC family related to different cancers. However, the nonselective profile of existing HDAC1 inhibitors restricted their clinical utility.

Biphenylsulfonamides as effective MMP-2 inhibitors with promising antileukemic efficacy: Synthesis, in vitro biological evaluation, molecular docking, and MD simulation analysis.

Overexpression of matrix metalloproteinase-2 (MMP-2) possesses a correlation with leukemia especially chronic myeloid leukemia (CML). However, no such MMP-2 inhibitor has come out in the market to date for treating leukemia. In this study, synthesis, biological evaluation, and molecular modeling studies of a set of biphenylsulfonamide derivatives as promising MMP-2 inhibitors were performed, focusing on their potential applications as antileukemic therapeutics.

A patent review of histone deacetylase 8 (HDAC8) inhibitors (2013-present).

Introduction: The processes and course of several fatal illnesses, such as cancer, inflammatory diseases, and neurological disorders are closely correlated with HDAC8. Therefore, novel HDAC8 inhibitors represent effective therapeutic possibilities that may help treat these conditions. To yet, there are not any such particular HDAC8 inhibitors available for sale.

Derivatives of D(-) glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-I: Synthesis, biological screening and in silico binding interaction analysis.

Chronic myeloid leukemia (CML) is a global issue and the available drugs such as tyrosine kinase inhibitors (TKIs) comprise various toxic effects as well as resistance and cross-resistance. Therefore, novel molecules targeting specific enzymes may unravel a new direction in antileukemic drug discovery. In this context, targeting gelatinases (MMP-2 and MMP-9) can be an alternative option for the development of novel molecules effective against CML.

Fragment-based discovery of new potential DNMT1 inhibitors integrating multiple pharmacophore modeling, 3D-QSAR, virtual screening, molecular docking, ADME, and molecular dynamics simulation approaches.

DNA methyl transferases (DNMTs) are one of the crucial epigenetic modulators associated with a wide variety of cancer conditions. Among the DNMT isoforms, DNMT1 is correlated with bladder, pancreatic, and breast cancer, as well as acute myeloid leukemia and esophagus squamous cell carcinoma. Therefore, the inhibition of DNMT1 could be an attractive target for combating cancers and other metabolic disorders.

An assessment of crucial structural contributors of HDAC6 inhibitors through fragment-based non-linear pattern recognition and molecular dynamics simulation approaches.

Amidst the Zn-dependant isoforms of the HDAC family, HDAC6 has emerged as a potential target associated with an array of diseases, especially cancer and neuronal disorders like Rett's Syndrome, Alzheimer's disease, Huntington's disease, etc. Also, despite the availability of a handful of HDAC inhibitors in the market, their non-selective nature has restricted their use in different disease conditions. In this situation, the development of selective and potent HDAC6 inhibitors will provide efficacious therapeutic agents to treat different diseases.

A combined ligand-based and structure-based molecular modeling approach to pinpoint the key structural attributes of hydroxamate derivatives as promising meprin β inhibitors.

Human meprin β is a Zn-containing multidomain metalloprotease enzyme that belongs to the astacin family of the metzincin endopeptidase superfamily. Meprin β, with its diverse tissue expression pattern and wide substrate specificity, plays a significant role in various biological processes, including regulation of IL-6R pathways, lung fibrosis, collagen deposition, cellular migration, neurotoxic amyloid β levels, and inflammation. Again, meprin β is involved in Alzheimer's disease, hyperkeratosis, glomerulonephritis, diabetic kidney injury, inflammatory bowel disease, and cancer.

An updated patent review of matrix metalloproteinase (MMP) inhibitors (2021-present).

Introduction: Matrix metalloproteinases (MMPs) are strongly interlinked with the progression and mechanisms of several life-threatening diseases including cancer. Thus, novel MMP inhibitors (MMPIs) as promising drug candidates can be effective in combating these diseases. However, no MMPIs are marketed to date due to poor pharmacokinetics and lower selectivity.

A fragment-based exploration of diverse MMP-9 inhibitors through classification-dependent structural assessment.

Matrix metalloproteinases (MMPs) are belonging to the Zn-dependent metalloenzymes. These can degenerate the extracellular matrix (ECM) that is entailed with various biological processes. Among the MMP family members, MMP-9 is associated with several pathophysiological circumstances.

Pharmacophore-based virtual screening, 3D QSAR, Docking, ADMET, and MD simulation studies: An in silico perspective for the identification of new potential HDAC3 inhibitors.

Histone deacetylase 3 (HDAC3) is an epigenetic regulator that involves gene expression, apoptosis, and cell cycle progression, and the overexpression of HDAC3 is accountable for several cancers, neurodegeneracy, and many other diseases. Therefore, HDAC3 emerged as a promising drug target for the novel drug design. Here, we carried out the pharmacophore modeling using 50 benzamide-based HDAC3 selective inhibitors and utilized it for PHASE ligand screening to retrieve the hits with similar pharmacophore features.

Selective HDAC3 Inhibitors with Potent In Vivo Antitumor Efficacy against Triple-Negative Breast Cancer.

HDAC3 modulation shows promise for breast cancer, including triple-negative cases. Novel -hydrazide-based HDAC3 inhibitors were designed and synthesized. Lead compound exhibited potent HDAC3 inhibition (IC = 14 nM) with at least 121-fold selectivity.

Fragment-based structural exploration and chemico-biological interaction study of HDAC3 inhibitors through non-linear pattern recognition, chemical space, and binding mode of interaction analysis.

HDAC3 is an emerging target for the identification and discovery of novel drug candidates against several disease conditions including cancer. Here, a fragment-based non-linear machine learning (ML) method along with chemical space exploration followed by a structure-based binding mode of interaction analysis study was carried out on some HDAC3 inhibitors to obtain the key structural features modulating HDAC3 inhibition. Both the ML and chemical space analysis identified several physicochemical and structural properties namely lipophilicity, polar and relative polar surface area, arylcarboxamide moiety, bulky fused aromatic group, -alkyl, and cinnamoyl moieties, the higher number of oxygen atoms, π-electrons for the substituted tetrahydrofuronaphthodioxolone moiety favorable for higher HDAC3 inhibition.

Employing comparative QSAR techniques for the recognition of dibenzofuran and dibenzothiophene derivatives toward MMP-12 inhibition.

Among various matrix metalloproteinases (MMPs), MMP-12 is one of the potential targets for cancer and other diseases. However, none of the MMP-12 inhibitors has passed the clinical trials to date. Therefore, designing potential MMP-12 inhibitors as new drug molecules can provide effective therapeutic strategies for several diseases.

Hydrazides as Potential HDAC Inhibitors: Structure-activity Relationships and Biological Implications.

Epigenetic modulations by HDACs are associated with multiple disease conditions. In this context, HDACs play vital roles in the progression of diseases including several cancers, neurodegenerative diseases, inflammatory diseases, and metabolic disorders. Though several HDAC inhibitors have been established as drug candidates, their usage has been restricted because of broad-spectrum inhibition, highly toxic character, and off-target adverse effects.

Fragment-based investigation of thiourea derivatives as VEGFR-2 inhibitors: a cross-validated approach of ligand-based and structure-based molecular modeling studies.

Angiogenesis is mediated by the vascular endothelial growth factor (VEGF) that plays a key role in the modulation of progression, invasion and metastasis, related to solid tumors and hematological malignancies. Several small-molecule VEGFR-2 inhibitors are marketed, but their usage is restricted to specific cancers due to severe toxicities. Therefore, cost-effective novel small molecule VEGFR-2 inhibitors may be an alternative to overcome these adverse effects.

Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences.

COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19.

Selective Inhibitors of Medium-Size S1' Pocket Matrix Metalloproteinases: A Stepping Stone of Future Drug Discovery.

Among various matrix metalloproteinases (MMPs), MMPs having medium-size S1' pockets are established as promising biomolecular targets for executing crucial roles in cancer, cardiovascular diseases, and neurodegenerative diseases. However, no such MMP inhibitors (MMPIs) are available to date as drug candidates despite a lot of continuous research work for more than three decades. Due to a high degree of structural resemblance among these MMPs, designing selective MMPIs is quite challenging.

Selective inhibition of histone deacetylase 3 by novel hydrazide based small molecules as therapeutic intervention for the treatment of cancer.

A promising hydrazide based small molecule lead as a potent and selective histone deacetylase 3 (HDAC3) inhibitor has been developed from a small series of synthesized novel chemical entities. The lead compound (4e) displayed high HDAC3 inhibitory potency (IC = 15.41 nM) and a minimum of 18-fold selectivity over other HDAC isoforms.

A fragment-based structural analysis of MMP-2 inhibitors in search of meaningful structural fragments.

The matrix metalloproteinase family of Zn-dependent metalloenzymes are a group of proteases that possess the ability to degrade the extracellular matrix (ECM) and thus are involved in different biological processes. Being one of the prime members of this family, the matrix metalloproteinase-2 (MMP-2) is associated with several pathophysiological conditions including cancer, tumor progression, invasion, and metastasis. Due to its contribution toward human pathophysiology, MMP-2 is in the limelight of anticancer drug development research for more than three decades.