Modeling of FAK-PROTAC candidates from GSK2256098 analogs for targeted protein degradation.

Protein inhibition via the traditional drug-designing approach has been shown to be an effective method for developing numerous small-molecule-based therapeutics. In the last decade, small inhibitors-guided protein degradation has arisen as an alternative method with the potential to fulfill the drug requirement for undruggable targets. Focal adhesion kinase (FAK) is a crucial modulator of the growth and spread of tumors, apart from it also acts as a scaffold for signaling of other proteins.

Uncovering potential CDK9 inhibitors from natural compound databases through docking-based virtual screening and MD simulations.

Context: Cyclin-dependent kinase 9 (CDK9) plays a significant role in gene regulation and RNA polymerase II transcription under basal and stimulated conditions. The upregulation of transcriptional homeostasis by CDK9 leads to various malignant tumors and therefore acts as a valuable drug target in addressing cancer incidences. Ongoing drug development endeavors targeting CDK9 have yielded numerous clinical candidate molecules currently undergoing investigation as potential CDK9 modulators, though none have yet received Food and Drug Administration (FDA) approval.

C-Type LECTIN receptor-like kinase 1 and ACTIN DEPOLYMERIZING FACTOR 3 are key components of plasmodesmata callose modulation.

Plasmodesmata (PDs) are intercellular organelles carrying multiple membranous nanochannels that allow the trafficking of cellular signalling molecules. The channel regulation of PDs occurs dynamically and is required in various developmental and physiological processes. It is well known that callose is a critical component in regulating PD permeability or symplasmic connectivity, but the understanding of the signalling pathways and mechanisms of its regulation is limited.

Information Density Enhancement Using Lossy Compression in DNA Data Storage.

This study develops two deoxyribonucleic acid (DNA) lossy compression models, Models A and B, to encode grayscale images into DNA sequences, enhance information density, and enable high-fidelity image recovery. These models, distinguished by their handling of pixel domains and interpolation methods, offer a novel approach to data storage for DNA. Model A processes pixels in overlapped domains using linear interpolation (LI), whereas Model B uses non-overlapped domains with nearest-neighbor interpolation (NNI).

Computational insights into allosteric inhibition of focal adhesion kinase: A combined pharmacophore modeling and molecular dynamics approach.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that modulates integrin and growth factor signaling pathways and is implicated in cancer cell migration, proliferation, and survival. Over the past decade various, FAK kinase, FERM, and FAT domain inhibitors have been reported and a few kinase domain inhibitors are under clinical consideration. However, few of them were identified as multikinase inhibitors.

A review on Millepachine and its derivatives as potential multitarget anticancer agents.

Chalcones have a long history of being used for many medical purposes. These are the most prestigious scaffolds in medicine. The potential of Millepachine and its derivatives to treat various malignancies has been demonstrated in this review.

Repurposing and computational design of PARP inhibitors as SARS-CoV-2 inhibitors.

Coronavirus disease 2019 (COVID-19) is a recent pandemic that caused serious global emergency. To identify new and effective therapeutics, we employed a drug repurposing approach. The poly (ADP ribose) polymerase inhibitors were used for this purpose and were repurposed against the main protease (Mpro) target of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2).

Vutiglabridin Modulates Paraoxonase 1 and Ameliorates Diet-Induced Obesity in Hyperlipidemic Mice.

Vutiglabridin is a clinical-stage synthetic small molecule that is being developed for the treatment of obesity and its target proteins have not been fully identified. Paraoxonase-1 (PON1) is an HDL-associated plasma enzyme that hydrolyzes diverse substrates including oxidized low-density lipoprotein (LDL). Furthermore, PON1 harbors anti-inflammatory and antioxidant capacities and has been implicated as a potential therapeutic target for treating various metabolic diseases.

Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches.

The PI3K/Akt/mTOR is an essential intracellular signaling pathway in which the serine/threonine mTOR kinase portrays a major role in cell growth, proliferation and survival. The mTOR kinase is frequently dysregulated in a broad spectrum of cancers, thus making it a potential target. Rapamycin and its analogs (rapalogs) allosterically inhibit mTOR, thereby dodging the deleterious effects prompted by ATP-competitive mTOR inhibitors.

An overview on monkeypox virus: Pathogenesis, transmission, host interaction and therapeutics.

is one of the most notorious genus amongst the family. Monkeypox (MP) is a zoonotic disease that has been spreading throughout Africa. The spread is global, and incidence rates are increasing daily.

Explicit molecular dynamics simulation studies to discover novel natural compound analogues as inhibitors.

Tuberculosis (TB) in one of the dreadful diseases present globally. This is caused by . dethiobiotin synthetase (DTBS) is an essential enzyme in biotin biosynthesis and is an ideal target to design and develop novel inhibitors.

Protective effect of GK2 fused BLVRA protein against oxidative stress-induced dopaminergic neuronal cell damage.

It is well known that oxidative stress is highly associated with Parkinson's disease (PD), and biliverdin reductase A (BLVRA) is known to have antioxidant properties against oxidative stress. In this study, we developed a novel N-acetylgalactosamine kinase (GK2) protein transduction domain (PTD) derived from adenosine A2A and fused with BLVRA to determine whether the GK2-BLVRA fusion protein could protect dopaminergic neuronal cells (SH-SY5Y) from oxidative stress in vitro and in vivo using a PD animal model. GK2-BLVRA was transduced into various cells, including SH-SY5Y cells, without cytotoxic effects, and this fusion protein protected SH-SY5Y cells and reduced reactive oxygen species production and DNA damage after 1-methyl-4-phenylpyridinium (MPP ) exposure.

Pharmacophore-Oriented Identification of Potential Leads as CCR5 Inhibitors to Block HIV Cellular Entry.

Cysteine-cysteine chemokine receptor 5 (CCR5) has been discovered as a co-receptor for cellular entry of human immunodeficiency virus (HIV). Moreover, the role of CCR5 in a variety of cancers and various inflammatory responses was also discovered. Despite the fact that several CCR5 antagonists have been investigated in clinical trials, only Maraviroc has been licensed for use in the treatment of HIV patients.

Structural Insights and Development of LRRK2 Inhibitors for Parkinson's Disease in the Last Decade.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD.

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors.

Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib.

Inhibition of DDX3 and COX-2 by forskolin and evaluation of anti-proliferative, pro-apoptotic effects on cervical cancer cells: molecular modelling and in vitro approaches.

Several studies have reported up-regulation of both cyclooxygenase-2 (COX-2) and DEAD-box RNA helicase3 (DDX3) and have validated their oncogenic role in many cancers. Inhibition of COX-2 and DDX3 offers a potential pharmacological strategy for prevention of cancer progression. The COX-2 isoform is expressed in response to pro-inflammatory stimuli in premalignant lesions, including cervical tissues.

Investigating natural compounds against oncogenic RET tyrosine kinase using pharmacoinformatic approaches for cancer therapeutics.

Rearranged during transfection (RET) tyrosine kinase is a transmembrane receptor tyrosine kinase regulating vital aspects of cellular proliferation, differentiation, and survival. An outstanding challenge in designing protein kinase inhibitors is due to the development of drug resistance. The "gain of function" mutations in the RET gate-keeper residue, Val804, confers resistance to the majority of known RET inhibitors, including vandetanib.