MD-Ligand-Receptor: A High-Performance Computing Tool for Characterizing Ligand-Receptor Binding Interactions in Molecular Dynamics Trajectories.

Molecular dynamics simulation is a widely employed computational technique for studying the dynamic behavior of molecular systems over time. By simulating macromolecular biological systems consisting of a drug, a receptor and a solvated environment with thousands of water molecules, MD allows for realistic ligand-receptor binding interactions (lrbi) to be studied. In this study, we present MD-ligand-receptor (MDLR), a state-of-the-art software designed to explore the intricate interactions between ligands and receptors over time using molecular dynamics trajectories. Unlike traditional static analysis tools, MDLR goes beyond simply taking a snapshot of ligand-receptor binding interactions (lrbi), uncovering long-lasting molecular interactions and predicting the time-dependent inhibitory activity of specific drugs. With MDLR, researchers can gain insights into the dynamic behavior of complex ligand-receptor systems. Our pipeline is optimized for high-performance computing, capable of efficiently processing vast molecular dynamics trajectories on multicore Linux servers or even multinode HPC clusters. In the latter case, MDLR allows the user to analyze large trajectories in a very short time. To facilitate the exploration and visualization of lrbi, we provide an intuitive Python notebook (Jupyter), which allows users to examine and interpret the results through various graphical representations.

Molecular Dynamics Investigations of Human DNA-Topoisomerase I Interacting with Novel Dewar Valence Photo-Adducts: Insights into Inhibitory Activity.

Chronic exposure to ultraviolet (UV) radiation is known to induce the formation of DNA photo-adducts, including cyclobutane pyrimidine dimers (CPDs) and Dewar valence derivatives (DVs). While CPDs usually occur at higher frequency than DVs, recent studies have shown that the latter display superior selectivity and significant stability in interaction with the human DNA/topoisomerase 1 complex (TOP1). With the aim to deeply investigate the mechanism of interaction of DVs with TOP1, we report here four all-atom molecular dynamic simulations spanning one microsecond. These simulations are focused on the stability and conformational changes of two DNA/TOP1-DV complexes in solution, the data being compared with the biomimetic thymine dimer counterparts. Results from root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) analyses unequivocally confirmed increased stability of the DNA/TOP1-DV complexes throughout the simulation duration. Detailed interaction analyses, uncovering the presence of salt bridges, hydrogen bonds, water-mediated interactions, and hydrophobic interactions, as well as pinpointing the non-covalent interactions within the complexes, enabled the identification of specific TOP1 residues involved in the interactions over time and suggested a potential TOP1 inhibition mechanism in action.

Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of New Drugs against Human Topoisomerase I Receptor.

Human Topoisomerase I (hTop1p) is a ubiquitous enzyme that relaxes supercoiled DNA through a conserved mechanism involving transient breakage, rotation, and binding. Htop1p is the molecular target of the chemotherapeutic drug camptothecin (CPT). It causes the hTop1p-DNA complex to slow down the binding process and clash with the replicative machinery during the S phase of the cell cycle, forcing cells to activate the apoptotic response. This gives hTop1p a central role in cancer therapy. Recently, two artesunic acid derivatives (compounds c6 and c7) have been proposed as promising inhibitors of hTop1p with possible antitumor activity. We used several computational approaches to obtain in silico confirmations of the experimental data and to form a comprehensive dynamic description of the ligand-receptor system. We performed molecular docking analyses to verify the ability of the two new derivatives to access the enzyme-DNA interface, and a classical molecular dynamics simulation was performed to assess the capacity of the two compounds to maintain a stable binding pose over time. Finally, we calculated the noncovalent interactions between the two new derivatives and the hTop1p receptor in order to propose a possible inhibitory mechanism like that adopted by CPT.

Pressure-painful scalp arteries in children and adolescents suffering from migraine.

OBJECTIVE: This study aimed to evaluate the presence of pressure-painful scalp arteries in children and adolescents with migraine. MATERIALS AND METHODS: Pressure-painful points on scalp arteries were searched in 130 consecutive children (6-12 years old) and adolescents (>13 years old) affected with migraine, 89 females and 41 males, and in 40 age-matched controls. RESULTS: In the absence of a migraine episode, we examined 76 patients: 54 (71.1%) reported one or more pressure-painful arteries and 22 reported none. Of the 40 controls, pressure-painful arteries were present in 11, with a highly significant difference (p < 0.0001). During a migraine attack, of the 54 patients examined, 43 (79.6 %) reported one or more pressure-painful arteries and 11 reported none. The arteries most frequently painful were the frontal branch and the superficial temporal artery. CONCLUSIONS: Scalp arteries are frequently painful on pressure in children and adolescents with migraine, both in the absence of and during a migraine attack. Painful arteries suggest hypersensitivity of periarterial nociceptive afferents.

Transanal hemorrhoidal dearterialization: a systematic review.

PURPOSE: Transanal hemorrhoidal dearterialization consists of a Doppler-guided ligation of the distal branches of the rectal arteries. The aim of this review is to assess the current evidence on dearterialization, establish the safety and efficacy of the technique, define its indications, and identify its possible advantages and limitations. METHODS: All published studies on dearterialization without language restrictions were reviewed systematically. Primary outcome measures were postoperative pain and hemorrhoidal recurrences. RESULTS: Seventeen articles including a total of 1,996 patients were analyzed. In general, the quality of the studies was low. Operating time ranged between 5 and 50 minutes. Hospital stay was one day for most patients, whereas the return to normal activities was between two and three days in most cases. Postoperative pain was present in 18.5% of patients. Three patients experienced significant postoperative hemorrhages. There were no other major complications. The overall recurrence rate was 9.0% for prolapse, 7.8% for bleeding, and 4.7% for pain at defecation. The recurrence rate at one year or more was 10.8% for prolapse, 9.7% for bleeding, and 8.7% for pain at defecation. When reported as a function of the hemorrhoidal grade, the recurrence rate was higher for fourth-degree hemorrhoids (range, 11.1-59.3%). CONCLUSION: Transanal hemorrhoidal dearterialization appears to be a potential treatment option for second-degree and third-degree hemorrhoids. Clinical trials and longer follow-up comparing it with other procedures used to treat hemorrhoids are needed to establish a possible role for this technique.

Do pure absence seizures occur in myoclonic epilepsy of infancy? A case series.

PURPOSE: To assess if absence seizures (ASs) occur in patients with myoclonic epilepsy of infancy (MEI). METHODS: A retrospective chart review was conducted in 37 patients with MEI followed at seven different paediatric epilepsy centres in Italy, between 2002 and 2014. To assess the possible occurrence of pure ASs or absences associated with myoclonias, ASs were defined according to the following criteria: (i) a sudden onset and interruption of ongoing activities; (ii) bilateral polyspikes or spike-and-wave (SW) complexes; spike SW complexes at 2-4Hz; (iii) duration of AS: 3-30seconds. RESULTS: Thirty-seven MEI patients (25 boys and 12 girls) were identified. Nine patients (24.3%) had a history of simple FS during the first year of life. Ten patients (27%) had a family history of epilepsy, and six patients (16.2%) had a family history of FS. In 7/37 (18.9%) patients, during the occurrence of MSs, a total of nineteen brief ASs were captured by video-EEG recordings. ASs occurred both during a brief cluster of rhythmic MSs than after single myoclonic jerks. The ictal EEG abnormalities observed in patients with ASs were similar to the ictal EEG patterns associated with only myoclonias. No differences in relation to gender, family history, ictal EEG discharge were found between patients with myoclonic seizures with ASs and myoclonias without ASs. CONCLUSIONS: Absence seizures can occur in approximately 20% of MEI patients and the occurrence of ASs, though not essential to formulate the diagnosis, do not automatically exclude the diagnosis of MEI.

Painful scalp arteries in migraine.

Previous studies suggest a role of scalp perivascular structures in at least a substantial number of migraineurs. This study aimed to evaluate the presence of pressure-painful scalp arteries in patients with migraine. Pressure-painful points on scalp arteries were searched for in 100 consecutive patients affected with migraine, 84 females (F) and 16 males (M), 83 without aura (70 F) and 17 with aura (14 F), and in 30 healthy matched subjects. The examined arteries were, bilaterally, the superficial temporal and its frontal branch, the zygomatico-orbital, the occipital and the posterior auricular. We examined 75 patients interictally: 60 (80.0%) reported one or more (mean per subject 3.7 ± 1.9) pressure-painful arteries and 15 (20.0%) reported none. In the 30 controls, pressure-painful arteries were present in only nine (30.0%, mean per subject 1.3 ± 0.7), with highly significant differences (p < 0.001). During a migraine attack, of the 51 patients examined, 45 (88.2%, 38F) reported one or more (mean 3.8 ± 2.1) pressure-painful arteries and six (11.8%) reported none. Both when during an attack and interictally, the arteries most frequently involved were the occipital, the frontal branch, and the temporal. Scalp arteries are frequently painful to pressure in migraineurs, especially in females, both during headache and interictally. Painful arteries suggest hypersensitivity of periarterial nociceptive afferents, which is perhaps due to the local presence of endogenous algogenic products, as suggested by our previous studies.