In silico assessment of a natural small molecule as an inhibitor of programmed death ligand 1 for cancer immunotherapy: a computational approach.

Programmed cell death ligand 1 (PD-L1) is a crucial target for cancer therapy. Here, an in silico study investigates PD-L1 to inhibit its interaction with PD1, thereby promoting an immune response to eliminate cancer cells. The study employed machine learning (ML) -based QSAR to detect PDL1 inhibitors. Morgan's fingerprint with docking score showed a 0.83 correlation with the experimental IC50, enabling the screening of 3200 natural compounds. The top three compounds, considered 2819, 2821 and 3188, were selected from the ML-based QSAR and subjected to molecular docking and simulation. The binding scores for 2819, 2821 and 3188 were -7.0, -9.0 and -8.9 kcal/mol, respectively. The stability of the ligands during a 100 ns simulation was assessed using RMSD, showing that 2819 and 2821 maintained stable patterns comparable to the control inhibitor. Notably, 2819 exhibited a consistent stable pattern throughout the simulation, while 2821 showed stability in the last 40 ns. The control compound showed the highest number of hydrogen bonds with proteins, whereas compounds 2819 and 2821 formed continuous H-bonds. 3188 was separated from the protein in later phases and is not regarded as a potential PD-L1-binding molecule. MMGBSA binding free energy for complexes was computed. Control had the lowest binding free energy, while 2819 and 2821 also had lower binding energies. In contrast, 3188 showed poor binding free energy, causing protein separation. Principal component analysis showed a loss of entropy and reduced protein conformational variation. Overall, 2819 and 2821 are potential binders for PD-L1 inhibition and immune response triggering.Communicated by Ramaswamy H. Sarma.

Discovery of Rift Valley fever virus natural pan-inhibitors by targeting its multiple key proteins through computational approaches.

The Rift Valley fever virus (RVFV) is a zoonotic arbovirus and pathogenic to both humans and animals. Currently, no proven effective RVFV drugs or licensed vaccine are available for human or animal use. Hence, there is an urgent need to develop effective treatment options to control this viral infection. RVFV glycoprotein N (GN), glycoprotein C (GC), and nucleocapsid (N) proteins are attractive antiviral drug targets due to their critical roles in RVFV replication. In present study, an integrated docking-based virtual screening of more than 6000 phytochemicals with known antiviral activities against these conserved RVFV proteins was conducted. The top five hit compounds, calyxin C, calyxin D, calyxin J, gericudranins A, and blepharocalyxin C displayed optimal binding against all three target proteins. Moreover, multiple parameters from the molecular dynamics (MD) simulations and MM/GBSA analysis confirmed the stability of protein-ligand complexes and revealed that these compounds may act as potential pan-inhibitors of RVFV replication. Our computational analyses may contribute toward the development of promising effective drugs against RVFV infection.

Muscle protein synthesis and muscle/metabolic responses to resistance exercise training in South Asian and White European men.

The aims of the current study, therefore, were to compare (1) free-living MPS and (2) muscle and metabolic adaptations to resistance exercise in South Asian and white European adults. Eighteen South Asian and 16 White European men were enrolled in the study. Free-living muscle protein synthesis was measured at baseline. Muscle strength, body composition, resting metabolic rate, VO2max and metabolic responses (insulin sensitivity) to a mixed meal were measured at baseline and following 12 weeks of resistance exercise training. Free-living muscle protein synthesis was not different between South Asians (1.48 ± 0.09%/day) and White Europeans (1.59 ± 0.15%/day) (p = 0.522). In response to resistance exercise training there were no differences, between South Asians and White Europeans, muscle mass, lower body strength or insulin sensitivity. However, there were differences between the ethnicities in response to resistance exercise training in body fat, resting carbohydrate and fat metabolism, blood pressure, VO2max and upper body strength with responses less favourable in South Asians. In this exploratory study there were no differences in muscle protein synthesis or anabolic and metabolic responses to resistance exercise, yet there were less favourable responses in several outcomes. These findings require further investigation.

The effect of short-duration resistance training on insulin sensitivity and muscle adaptations in overweight men.

NEW FINDINGS: What is the central question of this study? What is the time course of muscular adaptations to short-duration resistance exercise training? What is the main finding and its importance? Short-duration resistance training results in early and progressive increases in muscle mass and function and an increase in insulin sensitivity. ABSTRACT: The aim of the study was to investigate the effects of 6 weeks of resistance exercise training, composed of one set of each exercise to voluntary failure, on insulin sensitivity and the time course of adaptations in muscle strength/mass. Ten overweight men (age 36 ± 8 years; height 175 ± 9 cm; weight 89 ± 14 kg; body mass index 29 ± 3 kg m-2 ) were recruited to the study. Resistance exercise training involved three sessions per week for 6 weeks. Each session involved one set of nine exercises, performed at 80% of one-repetition maximum to volitional failure. Sessions lasted 15-20 min. Oral glucose tolerance tests were performed at baseline and post-intervention. Vastus lateralis muscle thickness, knee-extensor maximal isometric torque and rate of torque development (measured between 0 and 50, 0 and 100, 0 and 200, and 0 and 300 ms) were measured at baseline, each week of the intervention, and after the intervention. Resistance training resulted in a 16.3 ± 18.7% (P < 0.05) increase in insulin sensitivity (Cederholm index). Muscle thickness, maximal isometric torque and one-repetition maximum increased with training, and at the end of the intervention were 10.3 ± 2.5, 26.9 ± 8.3, 18.3 ± 4.5% higher (P < 0.05 for both) than baseline, respectively. The rate of torque development at 50 and 100 ms, but not at 200 and 300 ms, increased (P < 0.05) over the intervention period. Six weeks of single-set resistance exercise to failure results in improvements in insulin sensitivity and increases in muscle size and strength in young overweight men.