A small molecule enhances arrestin-3 binding to the β-adrenergic receptor.

G protein-coupled receptor (GPCR) signaling is terminated by arrestin binding to a phosphorylated receptor. Binding propensity has been shown to be modulated by stabilizing the pre-activated state of arrestin through point mutations or C-tail truncation. Here, we hypothesize that pre-activated rotated states can be stabilized by small molecules, and this can promote binding to phosphorylation-deficient receptors, which underly a variety of human disorders.

Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.

Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge.

Residues in the fructose-binding pocket are required for ketohexokinase-A activity.

Excessive fructose consumption is a primary contributor to the global surges in obesity, cancer, and metabolic syndrome. Fructolysis is not robustly regulated and is initiated by ketohexokinase (KHK). In this study, we determined the crystal structure of KHK-A, one of two human isozymes of KHK, in the apo-state at 1.

Costing of a Combination Intervention (Kyaterekera) Addressing Sexual Risk-Taking Behaviors among Vulnerable Women in Southern Uganda.

In Uganda, women engaged in sex work (WESW) are a marginalized population at the intersection of multiple vulnerabilities. The Kyaterekera intervention is targeted at WESW in Rakai and the greater Masaka regions in Uganda and combines a traditional HIV risk-reduction approach with a savings-led economic empowerment intervention and financial literacy training. We estimated the economic costs of the Kyaterekera intervention from a program provider perspective using a prospective activity-based micro-costing method.

Dual activity of Minnelide chemosensitize basal/triple negative breast cancer stem cells and reprograms immunosuppressive tumor microenvironment.

Triple negative breast cancer (TNBC) subtype is characterized with higher EMT/stemness properties and immune suppressive tumor microenvironment (TME). Women with advanced TNBC exhibit aggressive disease and have limited treatment options. Although immune suppressive TME is implicated in driving aggressive properties of basal/TNBC subtype and therapy resistance, effectively targeting it remains a challenge.

Synthesis, Structural Investigations, DNA/BSA Interactions, Molecular Docking Studies, and Anticancer Activity of a New 1,4-Disubstituted 1,2,3-Triazole Derivative.

We report herein a new 1,2,3-triazole derivative, namely, 4-((1-(3,4-dichlorophenyl)-1-1,2,3-triazol-4-yl)methoxy)-2-hydroxybenzaldehyde, which was synthesized by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The structure of the compound was analyzed using Fourier transform infrared spectroscopy (FTIR), H NMR, C NMR, UV-vis, and elemental analyses. Moreover, X-ray crystallography studies demonstrated that the compound adapted a monoclinic crystal system with the 2/ space group.

Nonlocal Effects of Antibiotic-Resistance-Causing Mutations Reveal an Alternative Region for Targeting on FtsW-Penicillin-Binding Protein 3 Complex of .

Currently prescribed antibiotics target the catalytic sites of wild-type bacterial proteins; however, bacteria adopt mutations at this site, eventually leading to the emergence of resistance. Therefore, the identification of alternative drug binding sites is crucial, which requires knowledge of the dynamics of the mutant protein. Here, we set out to investigate the impact of a high-resistance-causing triple mutation (S385T + L389F + N526K) on the dynamics of a prioritized resistant pathogen, , using computational techniques.

Inhibition of mutant RAS-RAF interaction by mimicking structural and dynamic properties of phosphorylated RAS.

Undruggability of RAS proteins has necessitated alternative strategies for the development of effective inhibitors. In this respect, phosphorylation has recently come into prominence as this reversible post-translational modification attenuates sensitivity of RAS towards RAF. As such, in this study, we set out to unveil the impact of phosphorylation on dynamics of HRAS and aim to invoke similar behavior in HRAS mutant by means of small therapeutic molecules.

Mechanistic insight into impact of phosphorylation on the enzymatic steps of farnesyltransferase.

Farnesyltransferase (FTase) is a heterodimeric enzyme, which catalyzes covalent attachment of the farnesyl group to target proteins, thus coordinating their trafficking in the cell. FTase has been demonstrated to be highly expressed in cancer and neurological diseases; hence considered as a hot target for therapeutic purposes. However, due to the nonspecific inhibition, there has been only one inhibitor that could be translated into the clinic.

Experimental and Computational Investigation of Clustering Behavior of Cyclodextrin-Perfluorocarbon Inclusion Complexes as Effective Histotripsy Agents.

Recently developed nanocones (NCs), which are inclusion complexes that are made up of cyclodextrins (CDs) and perfluorocarbons (PFCs), have shown promising results in nanoparticle-mediated histotripsy (NMH) applications due to stable inclusion complexation, PFC quantification, simple synthesis, and processing. FDA-approved βCD and its modified versions such as low-degree methylated βCD have been previously demonstrated as prime examples of structures capable of accommodating PFC molecules. However, the complex formation potential of different CDs with various cavity sizes in the presence of PFC molecules, and their consequent aggregation, needs to be explored.

Mechanistic insight into the impact of a bivalent ligand on the structure and dynamics of a GPCR oligomer.

Development of effective bivalent ligands has become the focus of intensive research toward modulation of G protein-coupled receptor (GPCR) oligomers, particularly in the field of GPCR pharmacology. Experimental studies have shown that they increased binding affinity and signaling potency compared to their monovalent counterparts, yet underlying molecular mechanism remains elusive. To address this, we performed accelerated molecular dynamics simulations on bivalent-ligand bound Adenosine 2A receptor (AR) dimer in the context of a modeled tetramer, which consists of AR and dopamine 2 receptor (DR) homodimers and their cognate G proteins.

Dimethyl sulfoxide reduces the stability but enhances catalytic activity of the main SARS-CoV-2 protease 3CLpro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19), one of the most challenging global pandemics of the modern era. Potential treatment strategies against COVID-19 are yet to be devised. It is crucial that antivirals that interfere with the SARS-CoV-2 life cycle be identified and developed.

Inhibition of SARS-CoV-2 main protease: a repurposing study that targets the dimer interface of the protein.

Coronavirus disease-2019 (COVID-19) was firstly reported in Wuhan, China, towards the end of 2019, and emerged as a pandemic. The spread and lethality rates of the COVID-19 have ignited studies that focus on the development of therapeutics for either treatment or prophylaxis purposes. In parallel, drug repurposing studies have also come into prominence.

The single nucleotide β -arrestin2 variant, A248T, resembles dynamical properties of activated arrestin.

β -arrestins are responsible for termination of G protein-coupled receptor (GPCR)-mediated signaling. Association of single nucleotide variants with onset of crucial diseases has made this protein family hot targets in the field of GPCR-mediated pharmacology. However, impact of these mutations on function of these variants has remained elusive.

Linker residues regulate the activity and stability of hexokinase 2, a promising anticancer target.

Hexokinase (HK) catalyzes the first step in glucose metabolism, making it an exciting target for the inhibition of tumor initiation and progression due to their elevated glucose metabolism. The upregulation of hexokinase-2 (HK2) in many cancers and its limited expression in normal tissues make it a particularly attractive target for the selective inhibition of cancer growth and the eradication of tumors with limited side effects. The design of such safe and effective anticancer therapeutics requires the development of HK2-specific inhibitors that will not interfere with other HK isozymes.

In Silico Analysis of a Highly Mutated Gene in Cancer Provides Insight into Abnormal mRNA Splicing: Splicing Factor 3B Subunit 1 Mutant.

Cancer is the second leading cause of death worldwide. The etiology of the disease has remained elusive, but mutations causing aberrant RNA splicing have been considered one of the significant factors in various cancer types. The association of aberrant RNA splicing with drug/therapy resistance further increases the importance of these mutations.

Perturb-Scan-Pull: A Novel Method Facilitating Conformational Transitions in Proteins.

Conformational transitions in proteins facilitate precise physiological functions. Therefore, it is crucial to understand the mechanisms underlying these processes to modulate protein function. Yet, studying structural and dynamical properties of proteins is notoriously challenging due to the complexity of the underlying potential energy surfaces (PES).

Catalytically Competent Non-transforming H-RAS Mutant Provides Insight into Molecular Switch Function and GAP-independent GTPase Activity of RAS.

RAS mutants have been extensively studied as they are associated with development of cancer; however, H-RAS mutant has remained untouched since it does not lead to transformation in the cell. To the best of our knowledge, this is the first study where structural/dynamical properties of H-RAS have been investigated -in comparison to H-RAS, H-RAS, RAF-RBD-bound and GAP-bound H-RAS- using molecular dynamics simulations (total of 9 μs). We observed remarkable differences in dynamics of Y32.

Utilization of Biased G Protein-Coupled ReceptorSignaling towards Development of Safer andPersonalized Therapeutics.

G protein-coupled receptors (GPCRs) are involved in a wide variety of physiologicalprocesses. Therefore, approximately 40% of currently prescribed drugs have targeted this receptorfamily. Discovery of -arrestin mediated signaling and also separability of G protein and b-arrestinsignaling pathways have switched the research focus in the GPCR field towards development ofbiased ligands, which provide engagement of the receptor with a certain effector, thus enrichinga specific signaling pathway.

Computational Approaches in Antibody-drug Conjugate Optimization for Targeted Cancer Therapy.

Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells.

Prediction and Targeting of Interaction Interfaces in G-protein Coupled Receptor Oligomers.

Background: Communication within a protein complex is mediated by physical interactions made among the protomers. Evidence for both the allosteric regulation present among the protomers of the protein oligomer and of the direct effect of membrane composition on this regulation has made it essential to investigate the underlying molecular mechanism that drives oligomerization, the type of interactions present within the complex, and to determine the identity of the interaction interface. This knowledge allows a holistic understanding of dynamics and also modulation of the function of the resulting oligomers/signalling complexes.

Computational studies of G protein-coupled receptor complexes: Structure and dynamics.

G protein-coupled receptors (GPCRs) are ubiquitously expressed transmembrane proteins associated with a wide range of diseases such as Alzheimer's, Parkinson, schizophrenia, and also implicated in in several abnormal heart conditions. As such, this family of receptors is regarded as excellent drug targets. However, due to the high number of intracellular signaling partners, these receptors have a complex interaction networks and it becomes challenging to modulate their function.

Perturbation-Response Scanning Reveals Key Residues for Allosteric Control in Hsp70.

Hsp70 molecular chaperones play an important role in maintaining cellular homeostasis, and are implicated in a wide array of cellular processes, including protein recovery from aggregates, cross-membrane protein translocation, and protein biogenesis. Hsp70 consists of two domains, a nucleotide binding domain (NBD) and a substrate binding domain (SBD), each of which communicates via an allosteric mechanism such that the protein interconverts between two functional states, an ATP-bound open conformation and an ADP-bound closed conformation. The exact mechanism for interstate conversion is not as yet fully understood.