African derived phytocompounds may interfere with SARS-CoV-2 RNA capping machinery via inhibition of 2'-O-ribose methyltransferase: An in silico perspective.

Despite the ongoing vaccination against the life-threatening COVID-19, there is need for viable therapeutic interventions. The S-adenosyl-l-Methionine (SAM) dependent 2-O'-ribose methyltransferase (2'-O-MTase) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a therapeutic target against COVID-19 infection. In a bid to profile bioactive principles from natural sources, a custom-made library of 226 phytochemicals from African medicinal plants with especially anti-malarial activity was screened for direct interactions with SARS-CoV-2 2'-O-MTase (S2RMT) using molecular docking and molecular dynamics (MD) simulations as well as binding free energies methods. Based on minimal binding energy lower than sinefungin (a reference methyl-transferase inhibitor) and binding mode analysis at the catalytic site of S2RMT, a list of 26 hit phytocompounds was defined. The interaction of these phytocompounds was compared with the 2'-O-MTase of SARS-CoV and MERS-CoV. Among these compounds, the lead phytocompounds (LPs) viz: mulberrofuran F, 24-methylene cycloartenol, ferulate, 3-benzoylhosloppone and 10-hydroxyusambarensine interacted strongly with the conserved KDKE tetrad within the substrate binding pocket of the 2'-O-MTase of the coronavirus strains which is critical for substrate binding. The thermodynamic parameters analyzed from the MD simulation trajectories of the LPs-S2RMT complexes presented an eminent structural stability and compactness. These LPs demonstrated favorable druggability and in silico ADMET properties over a diverse array of molecular computing descriptors. The LPs show promising prospects in the disruption of S2RMT capping machinery in silico. However, these LPs should be validated via in vitro and in vivo experimental models.

Three-dimensional geometric morphometric analysis of the distal radius insertion sites of the palmar radiocarpal ligaments in hominoid primates.

OBJECTIVES: To identify anatomic differences in the insertion sites of the palmar radiocarpal ligaments in different species of hominoid primates that may be related to their different types of locomotion. MATERIALS AND METHODS: We have used three-dimensional geometric morphometrics (3D GM) to analyze the distal radius ligament insertion sites in 31 Homo sapiens, 25 Pan troglodytes, 31 Gorilla gorilla, and 15 Pongo pygmaeus. We have also dissected the radioscaphocapitate (RSC), long radiolunate (LRL) and short radiolunate (SRL) ligaments in six H. sapiens and five P. troglodytes to obtain quantitative values that were then compared with the results of the 3D GM analysis. RESULTS: H. sapiens had a relatively larger insertion site of the RSC + LRL ligament than the other hominoid primates. P. pygmaeus and P. troglodytes had a relatively large SRL ligament insertion site with a palmar orientation. In G. gorilla, the two ligament insertion sites were relatively smaller and the SRL insertion site had an ulnopalmar orientation. DISCUSSION: The morphological differences observed can be related to the types of locomotion used by the different species and to quantitative data obtained from the dissection of ligaments in H. sapiens and P. troglodytes. 3D GM analysis of ligament insertion sites can help in interpreting the types of locomotion used by extinct hominoid primates through the analysis of preserved fossilized fragments of the distal radius.

Three-dimensional computer simulations of feeding behaviour in red and giant pandas relate skull biomechanics with dietary niche partitioning.

The red (Ailurus fulgens) and giant (Ailuropoda melanoleuca) pandas are mammalian carnivores convergently adapted to a bamboo feeding diet. However, whereas Ailurus forages almost entirely on younger leaves, fruits and tender trunks, Ailuropoda relies more on trunks and stems. Such difference in foraging mode is considered a strategy for resource partitioning where they are sympatric. Here, we use finite-element analysis to test for mechanical differences and similarities in skull performance between Ailurus and Ailuropoda related to diet. Feeding simulations suggest that the two panda species have similar ranges of mechanical efficiency and strain energy profiles across the dentition, reflecting their durophagous diet. However, the stress distributions and peaks in the skulls of Ailurus and Ailuropoda are remarkably different for biting at all tooth locations. Although the skull of Ailuropoda is capable of resisting higher stresses than the skull of Ailurus, the latter is able to distribute stresses more evenly throughout the skull. These differences in skull biomechanics reflect their distinct bamboo feeding preferences. Ailurus uses repetitive chewing in an extended mastication to feed on soft leaves, and Ailuropoda exhibits shorter and more discrete periods of chomp-and-swallow feeding to break down hard bamboo trunks.

The morphofunctional implications of the glenoid labrum of the glenohumeral joint in hominoids.

OBJECTIVES: A morphocline of the glenoid cavity has been used to infer differences in locomotor behaviors; however, the glenoid cavity is surrounded by the glenoid labrum, a fibrocartilaginous structure that could influence the functionality of the glenoid. The objectives of this study are to explore the effects of the glenoid labrum on the area, depth, and morphology of the glenoid cavity in primates. MATERIALS AND METHODS: Photogrammetry was used to build 3D models of the glenoid, with and without the labrum, and three- (3D) and two-dimensional (2D) geometric morphometrics (GM) was applied. 2D areas were collected from zenithal images for glenoids with and without labrum to evaluate the availability of articular surface area. RESULTS: In the 2D GM the morphocline is present in the dry-bone sample but not with the presence of the glenoid labrum. In the 3D GM there are differences between species mainly concerning the depth of the glenoid cavity. 2D areas reveal that the amount of articular area of the glenoid cavity increases with the presence of the labrum, particularly in humans. DISCUSSION: The glenoid labrum changes the shape, increases the depth and the surface area of the glenoid cavity, particularly in humans. Therefore, the glenoid labrum might hold a functional role, increasing the stability of the glenohumeral joint of primates in general, and especially in humans.

Antimalarial phytochemicals as potential inhibitors of SARS-CoV-2 guanine N7-methyltransferase (nsp 14): an integrated computational approach.

The inhibition of capping enzymes such as guanine-N7-methyltransferase (GMT) is an attractive target for regulating viral replication, transcription, virulence, and pathogenesis. Thus, compounds that target the Severe Acute Respiratory Syndrome Corona Virus 2 GMT (S2GMT) will enhance drug development against COVID-19. In this study, an in-house library of 249 phytochemicals from African medicinal plants was screened using computational approaches including homology modeling, molecular docking, molecular dynamic simulations, binding free energy calculations based on molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) analysis for inhibitors of S2GMT. The top-ten ranked phytochemicals (TTRP) obtained from the docking analysis to S2GMT were further docked to SARS-COV N7-MTase. Among the TTRP, the top-four ranked phytocompounds (TFRP) viz: 3 alkaloids (Isocryptolepine, 10'-Hydroxyusambarensine and Isostrychnopentamine) and a flavonoid (Mulberrofuran F) interacted strongly with critical catalytic residues whose interference either reduce or completely abolish N7-MTase activity, indicating their potential as capping machinery disruptors. The interactions of TFRP with the catalytic residues of S2GMT were preserved in a 100 ns simulated dynamic environment, thereby, demonstrating high degree of structural stability. The MMPBSA binding free energy calculations corroborated the docking scores with biscryptolepine having the highest binding free energy to S2GMT. The TFRP showed favourable drug-likeness and ADMET properties over a wide range of molecular descriptors. Therefore, the TFRP can be further explored as potential S2GMT inhibitors in in vitro and in vivo experiments.Communicated by Ramaswamy H. Sarma.

Implications of the functional anatomy of the hand and forearm of Ailurus fulgens (Carnivora, Ailuridae) for the evolution of the 'false-thumb' in pandas.

Both the giant panda (Ailuropoda melanoleuca) and the red panda (Ailurus fulgens) possess a 'false-thumb', actually an enlarged radial sesamoid bone, which contributes to the gripping action of the hand. These species are not closely related, however, as one is an ursid and the other an ailurid, so the fact that they share this adaptation implies a remarkable convergence. We studied the functional anatomy of this structure in the red panda, comparing it with existing descriptions of the grasping mechanism in both pandas. Previous interpretations of the radial sesamoid in Ailurus as a rod-like structure without direct articulation to the wrist bones are inaccurate. There are various important differences between the red panda and the giant panda. In the former, the lesser development of the radial sesamoid, its connection with the flexor retinaculum, the presence of an insertion of the muscle abductor pollicis longus in the first metacarpal, which enhances its supinatory action, and the presence of a muscle flexor brevis digitorum manus point to thin-branch climbing features serving as an exaptation to the more recent role of the red panda hand in the manipulation of bamboo.