Design, synthesis and in vitro cell-free/cell-based biological evaluations of novel ERCC1-XPF inhibitors targeting DNA repair pathway

1 year ago
The structure-specific ERCC1-XPF endonuclease is essential for repairing bulky DNA lesions and helix distortions induced by UV radiation, which forms cyclobutane pyrimidine dimers (CPDs), or chemicals that crosslink DNA strands such as cyclophosphamide and platinum-based chemotherapeutic agents. Inhibition of the ERCC1-XPF endonuclease activity has been shown to sensitize cancer cells to these chemotherapeutic agents. In this study, we have conducted a structure activity relationship analysis...
Ahmed H Elmenoufy

Comparative Analysis, Structural Insights, and Substrate/Drug Interaction of CYP128A1 in <em>Mycobacterium tuberculosis</em>

1 year ago
Cytochrome P450 monooxygenases (CYPs/P450s) are well known for their role in organisms' primary and secondary metabolism. Among 20 P450s of the tuberculosis-causing Mycobacterium tuberculosis H37Rv, CYP128A1 is particularly important owing to its involvement in synthesizing electron transport molecules such as menaquinone-9 (MK9). This study employs different in silico approaches to understand CYP128 P450 family's distribution and structural aspects. Genome data-mining of 4250 mycobacterial...
Nokwanda Samantha Ngcobo

The development of a targeted and more potent, anti-Inflammatory derivative of colchicine: Implications for gout

1 year 1 month ago
CONCLUSIONS: We provide evidence that colchicine can be rendered more potent atinhibiting MSU-induced neutrophil activation and inflammation using a rational drug design approach. The development of compounds such as CCI will provide more efficacious drugs that will not only alleviate gout patients of their painful inflammatory episodes at significantly lower doses than colchicine, but also be of potential therapeutic benefit for patients with other diseases treated with colchicine.
Guillaume Paré

Actin networks voltage circuits

1 year 1 month ago
Filaments of the cellular protein actin can form bundles, which can conduct ionic currents as well as mechanical and voltage solitons. These inherent properties can be utilized to generate computing circuits solely based on self-assembled actin bundle structures. Starting with experimentally observed networks of actin bundles, we model their network structure in terms of edges and nodes. We compute and discuss the main electrical parameters, considering the bundles as electrical wires with...
Stefano Siccardi

A search for the physical basis of the genetic code

1 year 2 months ago
DNA contains the genetic code, which provides complete information about the synthesis of proteins in every living cell. Each gene encodes for a corresponding protein but most of the DNA sequence is non-coding. In addition to this non-coding part of the DNA, there is another redundancy, namely a multiplicity of DNA triplets (codons) corresponding to code for a given amino acid. In this paper we investigate possible physical reasons for the coding redundancy, by exploring free energy...
S Arbabi Moghadam

Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design

1 year 3 months ago
The novel coronavirus whose outbreak took place in December 2019 continues to spread at a rapid rate worldwide. In the absence of an effective vaccine, inhibitor repurposing or de novo drug design may offer a longer-term strategy to combat this and future infections due to similar viruses. Here, we report on detailed classical and mixed-solvent molecular dynamics simulations of the main protease (Mpro) enriched by evolutionary and stability analysis of the protein. The results were compared with...
Maria Bzówka

Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents

1 year 3 months ago
Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549,...
Julia Krzywik

Cell death and survival due to cytotoxic exposure modelled as a two-state Ising system

1 year 3 months ago
Cancer chemotherapy agents are assessed for their therapeutic utility primarily by their ability to cause apoptosis of cancer cells and their potency is given by an IC50 value. Chemotherapy uses both target-specific and systemic-action drugs and drug combinations to treat cancer. It is important to judiciously choose a drug type, its dosage and schedule for optimized drug selection and administration. Consequently, the precise mathematical formulation of cancer cells' response to chemotherapy...
S Arbabi Moghadam

Personalized therapy design for systemic lupus erythematosus based on the analysis of protein-protein interaction networks

1 year 4 months ago
We analyzed protein expression data for Lupus patients, which have been obtained from publicly available databases. A combination of systems biology and statistical thermodynamics approaches was used to extract topological properties of the associated protein-protein interaction networks for each of the 291 patients whose samples were used to provide the molecular data. We have concluded that among the many proteins that appear to play critical roles in this pathology, most of them are either...
Elizabeth J Brant

<em>In silico</em> Investigations of the Mode of Action of Novel Colchicine Derivatives Targeting β-Tubulin Isotypes: A Search for a Selective and Specific β-III Tubulin Ligand

1 year 4 months ago
The cardinal role of microtubules in cell mitosis makes them interesting drug targets for many pharmacological treatments, including those against cancer. Moreover, different expression patterns between cell types for several tubulin isotypes represent a great opportunity to improve the selectivity and specificity of the employed drugs and to design novel compounds with higher activity only on cells of interest. In this context, tubulin isotype βIII represents an excellent target for...
Lorenzo Pallante

Liver Bioreactor Design Issues of Fluid Flow and Zonation, Fibrosis, and Mechanics: A Computational Perspective

1 year 4 months ago
Tissue engineering, with the goal of repairing or replacing damaged tissue and organs, has continued to make dramatic science-based advances since its origins in the late 1980's and early 1990's. Such advances are always multi-disciplinary in nature, from basic biology and chemistry through physics and mathematics to various engineering and computer fields. This review will focus its attention on two topics critical for tissue engineering liver development: (a) fluid flow, zonation, and drug...
Vahid Rezania

Synthesis, biological evaluation and molecular docking studies of new amides of 4-chlorothiocolchicine as anticancer agents

1 year 5 months ago
Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7,...
Greta Klejborowska

Using the Gibbs Function as a Measure of Human Brain Development Trends from Fetal Stage to Advanced Age

1 year 5 months ago
We propose to use a Gibbs free energy function as a measure of the human brain development. We adopt this approach to the development of the human brain over the human lifespan: from a prenatal stage to advanced age. We used proteomic expression data with the Gibbs free energy to quantify human brain's protein-protein interaction networks. The data, obtained from BioGRID, comprised tissue samples from the 16 main brain areas, at different ages, of 57 post-mortem human brains. We found a...
Edward A Rietman

Investigation of the Electrical Properties of Microtubule Ensembles under Cell-Like Conditions

1 year 5 months ago
Microtubules are hollow cylindrical polymers composed of the highly negatively-charged (~23e), high dipole moment (1750 D) protein α, β- tubulin. While the roles of microtubules in chromosomal segregation, macromolecular transport, and cell migration are relatively well-understood, studies on the electrical properties of microtubules have only recently gained strong interest. Here, we show that while microtubules at physiological concentrations increase solution capacitance, free tubulin has no...
Aarat P Kalra

Microtubules as Sub-Cellular Memristors

1 year 5 months ago
Memristors represent the fourth electrical circuit element complementing resistors, capacitors and inductors. Hallmarks of memristive behavior include pinched and frequency-dependent I-V hysteresis loops and most importantly a functional dependence of the magnetic flux passing through an ideal memristor on its electrical charge. Microtubules (MTs), cylindrical protein polymers composed of tubulin dimers are key components of the cytoskeleton. They have been shown to increase solution's ionic...
Jack A Tuszynski

Dataset on interactions of membrane active agents with lipid bilayers

1 year 5 months ago
We address drug interactions with lipids using in silico simulations and in vitro experiments. The data article provides extended explanations on molecular mechanisms behind membrane action of membrane-active agents (MAAs): antimicrobial peptides and chemotherapy drugs. Complete interpretation of the data is found in the associated original article 'charge-based interactions of antimicrobial peptides and general drugs with lipid bilayers' [1]. Data on molecular dynamic simulations of the drug...
Md Ashrafuzzaman

Computer-aided drug design of small molecule inhibitors of the ERCC1-XPF protein-protein interaction

1 year 7 months ago
The heterodimer of DNA excision repair protein ERCC-1 and DNA repair endonuclease XPF (ERCC1-XPF) is a 5'-3' structure-specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1-XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum-based and cross-linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In...
Francesco Gentile

Gibbs free energy of protein-protein interactions correlates with ATP production in cancer cells

1 year 7 months ago
In this paper, we analyze several cancer cell types from two seemingly independent angles: (a) the over-expression of various proteins participating in protein-protein interaction networks and (b) a metabolic shift from oxidative phosphorylation to glycolysis. We use large data sets to obtain a thermodynamic measure of the protein-protein interaction network, namely the associated Gibbs free energy. We find a strong inverse correlation between the percentage of energy production via oxidative...
Stefan M Golas

Charge-based interactions of antimicrobial peptides and general drugs with lipid bilayers

1 year 7 months ago
Membrane-active agents (MAAs), such as antimicrobial peptides (AMPs) and chemotherapy drugs (CDs), induce ion pores/channels inside lipid bilayer membrane, as confirmed by standard electrophysiology experiments. A novel experimental method is described which detects agents directly at the membrane as confirmed for MAAs, CDs and aptamers. MAAs exhibit characteristic 'charge based' interactions with lipids. Electrostatic (ES) and van der Waals (vdW) contributions to the interaction energies have...
Md Ashrafuzzaman

Signaling Complexity Measured by Shannon Entropy and Its Application in Personalized Medicine

1 year 8 months ago
Traditional approaches to cancer therapy seek common molecular targets in tumors from different patients. However, molecular profiles differ between patients, and most tumors exhibit inherent heterogeneity. Hence, imprecise targeting commonly results in side effects, reduced efficacy, and drug resistance. By contrast, personalized medicine aims to establish a molecular diagnosis specific to each patient, which is currently feasible due to the progress achieved with high-throughput technologies....
Alessandra J Conforte