Biology subjects

Tan, H.

Publications and source records attributed to Tan, H..

At least 91 records · Page 5Linked to original sources

bioRxiv2020

Spacing spheroids, curl-up and coiled neuritic plexus of the sacral spinal cord of aged dog: Hypothesis based on continued NADPH diaphorase histological observations

NADPH diaphorase (N-d) neurons distribute in spinal cord and function for visceral sensation and autonomic regulation. N-d positive neurons innervate pelvic organs. In previous investigation, we report that aging-related N-d body (ANB) in the lumbosacral spinal cord in aged rat and megaloneurite in the sacral spinal cord in aged dog. This article was a continued data report of aging-related N-d alterations in aged dog. N-d positivity in aged spinal cord has revealed a certain of morphological profiles in the spinal cord of several species. However, we still found some denoted N-d neurodegenerative changes that we failed to notice in our previous studies when re-examination of the sacral spinal cord of aged dog. In the horizontal section, spacing spheroids in the superficial laminae of the dorsal horn, curl-up and coiled neurites in the intermediate zone were detected in the sacral spinal cord. The ANB and vacuolar neurite were also detected. Vacuolar degeneration also occurred in the dorsal ganglia at the sacral segment. The curl-up and coiled neurites did not occur in the lumbothoracic segment, but the ANB and vacuolar neurite were scatteringly detected in in the lumbothoracic segment of aged dog. The results suggested that the N-d sensory inputs interrupted and disconnected with integration of autonomic centers and output circuits of regulating urogenital organs during the aging. These specialized profiles were speculated that the N-d neurite deterioration of visceral sensory circuit implicated dysfunction of pelvic organs in the aging. Megaloneurite and fiber dilation may make backward reasoning to N-d fiber architecture under normal condition.

neuroscience↗

bioRxiv2020

A draft genome assembly of the eastern banjo frog Limnodynastes dumerilii dumerilii (Anura: Limnodynastidae)

Amphibian genomes are usually challenging to assemble due to large genome size and high repeat content. The Limnodynastidae is a family of frogs native to Australia, Tasmania and New Guinea. As an anuran lineage that successfully diversified on the Australian continent, it represents an important lineage in the amphibian tree of life but lacks reference genomes. Here we sequenced and annotated the genome of the eastern banjo frog Limnodynastes dumerilii dumerilii to fill this gap. The total length of the genome assembly is 2.38 Gb with a scaffold N50 of 285.9 kb. We identified 1.21 Gb of non-redundant sequences as repetitive elements and annotated 24,548 protein-coding genes in the assembly. BUSCO assessment indicated that more than 94% of the expected vertebrate genes were present in the genome assembly and the gene set. We anticipate that this annotated genome assembly will advance the future study of anuran phylogeny and amphibian genome evolution.

genomics↗

bioRxiv2020

Visualizing synaptic plasticity in vivo by large-scale imaging of endogenous AMPA receptors

Elucidating how synaptic molecules such as AMPA receptors mediate neuronal communication and tracking their dynamic expression during behavior is crucial to understand cognition and disease, but current technological barriers preclude large-scale exploration of molecular dynamics in vivo. We have developed a suite of innovative methodologies that break through these barriers: a new knockin mouse line with fluorescently tagged endogenous AMPA receptors, two-photon imaging of hundreds of thousands of labeled synapses in behaving mice, and computer-vision-based automatic synapse detection. Using these tools, we can longitudinally track how the strength of synapses changes during behavior. We used this approach to generate an unprecedentedly detailed spatiotemporal map of synaptic plasticity underlying sensory experience. More generally, these tools can be used as an optical probe capable of measuring functional synapse strength across entire brain areas during any behavioral paradigm, describing complex system-wide changes with molecular precision.

neuroscience↗

bioRxiv2020

Pial surface CSF-contacting texture, subpial and funicular plexus in the thoracic spinal cord in monkey: NADPH diaphorase histological configuration

In spinal cord, white matter is distinguished from grey matter in that it contains ascending and descending axonal tracts. While grey matter gets concentrated with neuronal cell bodies. Notable cell bodies and sensory modality of cerebral spinal fluid (CSF) in white matter are still elusive in certain segment of the spinal cord. Monkey Spinal cord was examined by NADPH diaphorase (NADPH-d) histochemistry. We found that NADPH-d positive neurons clustered and featured flat plane in mediolateral funiculus in caudal thoracic and rostral lumber spinal cord, especially evident in the horizontal sections. Majority of NADPH-d funicular neurons were relatively large size and moderately-or lightly-stained neurons. In horizontal section, the multipolar processes of the neurons were thicker than that of regular other neurons. The processes oriented laterally or obliquely in the lateral funiculus. Some of neuronal cell bodies and proximal processes attached NADPH-d positive buttons or puncta. The neuronal processes interlaced network medially linked to lateral horn (intermediolateral nucleus, IML) and laterally to subpial region, in which formed subpial plexus with subpial NADPH-d neurons. Subpial plexus appeared to contacting externally with CSF. The subpial plexus patterned like round brackets located in lateromarginal pial surface. Compared with sympathetic IML in rostral thoracic segments and sacral parasympathetic IML, the funicular plexus configurated a specialized neuro-texture in caudal thoracic segments. The dendritic arbor of funicular neuron featured variety geometric plane shapes. The funicular plexus oriented exclusive layered flat-plane organization between lateral horn and subpial region in caudal thoracic and rostral lumber spinal cord. The subpial plexus may work as CSF sensor outside of spinal cord. The cluster of funicular neurons may function as locomotion sensor, besides visceral regulation. Different to periventricular CSF contacting or pericentral canal structures, NADPH-d funicular neurons and subpial plexus that located in the pial surface. With advantage of NADPH-d, we found funicular neurons which termed academically as funicular plexus and specialized localization for subpial structure we termed subpial plexus. The funicular texture was regarded as neuronal bridge between the interior CSF in the central canal and external CSF out of the pial surface.

neuroscience↗

bioRxiv2020

On the origin and evolution of RNA editing in metazoans

Extensive adenosine-to-inosine (A-to-I) editing of nuclear-transcribed RNAs is the hallmark of metazoan transcriptional regulation, and is fundamental to numerous biochemical processes. Here we explore the origin and evolution of this regulatory innovation, by quantifying its prevalence in 22 species that represent all major transitions in metazoan evolution. We provide substantial evidence that extensive RNA editing emerged in the common ancestor of extant metazoans. We find the frequency of RNA editing varies across taxa in a manner independent of metazoan complexity. Nevertheless, cis-acting features that guide A-to-I editing are under strong constraint across all metazoans. RNA editing seems to preserve an ancient mechanism for suppressing the more recently evolved repetitive elements, and is generally nonadaptive in protein-coding regions across metazoans, except for Drosophila and cephalopods. Interestingly, RNA editing preferentially target genes involved in neurotransmission, cellular communication and cytoskeleton, and recodes identical amino acid positions in several conserved genes across diverse taxa, emphasizing broad roles of RNA editing in cellular functions during metazoan evolution that have been previously underappreciated.

evolutionary biology↗

bioRxiv2019

NADPH diaphorase neuronal dystrophy in gracile nucleus, cuneatus nucleus and spinal trigeminal nucleus in aged rat

NADPH-diaphorase (N-d) activity is commonly used to identify NOS-ergic neurons. In our previous study, N-d positive neuritic dystrophy and spheroid termed aging-related N-d Body is discovered in the lumbosacral spinal cord in the normal aging rats. Histological studies also reveal that N-d positive neurodegenerative changes occur in the gracile nucleus. We re-examined N-d activity in gracile nucleus in aged rat. We found N-d positive neuritic dystrophy and spheroid also occurred in the cuneatus nucleus and spinal trigeminal nucleus. Besides regular coronal section, longitudinal oriented dystrophic neurites were detected in the sagittal and horizontal section in gracile nucleus and dorsal column. We fziurther examined the medullary oblongata with regular classical histology including Golgi staining, immunocytochemistry of NOS and phosphorylated tau protein, neuronal tracing method with wheat germ agglutinin conjugated alexa-fluor-488 through sciatic nerve, and spinal cord transection at thoracic level. Most of N-d positive neuritic dystrophy and spheroid did not showed colocalization with NOS or phosphorylated tau protein. Neuronal tracing and spinal cord transection revealed that N-d dystrophic neurites in gracile nucleus originated from terminal of sensory projection from spinal cord and peripheral somatic input. The results suggested that aging-related N-d dystrophy in the gracile nucleus was unique morphological feature. In conclusion, it was postulated that the N-d dystrophy as a morphological marker of aging degenerative damage in normal aged organisms.

neuroscience↗

bioRxiv2019

A novel pathway linking plasma membrane and chloroplasts is co-opted by pathogens to suppress salicylic acid-dependent defences

Chloroplasts are crucial players in the activation of defensive hormonal responses during plant-pathogen interactions. Here, we show that a plant virus-encoded protein re-localizes from the plasma membrane to chloroplasts upon triggering plant defence, interfering with the chloroplast-dependent activation of anti-viral salicylic acid (SA) biosynthesis. Strikingly, we have found that plant pathogens from different kingdoms seem to have convergently evolved to target chloroplasts and impair SA-dependent defences following an association with membranes, which is based on the co-existence of two subcellular targeting signals, an N-myristoylation site and a chloroplast transit peptide. This pattern is also present in plant proteins, at least one of which conversely activates SA defences from the chloroplast. Taken together, our results suggest that a pathway linking plasma membrane to chloroplasts and activating defence exists in plants, and that such pathway has been co-opted by plant pathogens during host-pathogen co-evolution to promote virulence through suppression of SA responses.

plant biology↗

bioRxiv2019

Dynamic changes in rhythmic and arrhythmic neural signatures in the subthalamic nucleus induced by anaesthesia and intubation

BackgroundSubcortical structures including the basal ganglia have been proposed to be crucial for arousal, consciousness, and behavioural responsiveness. However, how basal ganglia contributes to the loss and recovery of consciousness during anaesthesia has not been well characterized.\n\nMethodsIn this study, using local field potentials (LFPs) from subthalamic nucleus (STN) and scalp electroencephalogram in 12 Parkinsons disease patients, we investigate STN neural signatures during propofol general anaesthesia and during intubation as an arousal intervention in anaesthesia.\n\nResultsPropofol-induced anaesthesia resulted in changes in multiple frequency bands in STN LFPs, including increased low-frequency activities (slow-wave oscillation, delta, theta, and alpha bands) and decreased higher-frequency activities. This was also accompanied by increased STN-frontal cortical coherence in alpha frequency band. Beta and high-gamma activities in the STN temporally increased during intubation compared to the status of loss of consciousness. We also show that the dynamic changes in the high frequency activities (80-180 Hz) in STN LFPs induced by propofol and intubation correlated with power-law exponent in the power spectra between 2 and 80 Hz.\n\nConclusionsOur findings suggest that anaesthesia and intubation induced changes in the STN LFPs in multiple frequency bands. They are also consistent with the hypothesis that the power-law exponent in the power spectra between 2 and 80 Hz reflect the excitation/inhibition balance in the STN, which is modulated by anaesthesia and intubation, and further modulate the high frequency activity.

neuroscience↗

bioRxiv2019

Structural basis of recruitment of RBM39 to DCAF15 by a sulfonamide molecular glue E7820

E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. In order to understand their mechanism of action, we carried out kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the 1 helix of RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other protein of interests.

biophysics↗

bioRxiv2019

Megaloneurite, a giant neurite of vasoactive intestinal peptide and nitric oxide synthase in the aged dog and identification by human sacral spinal cord

Megaloneurite of NADPH diaphorase (NADPH-d) positivity is a new kind of aging-related neurodegeneration and also co-localized with vasoactive intestinal peptide (VIP) in the sacral spinal cord of aged dog and monkey. However, no immunocytochemistry of VIP was exclusively tested in the aged dog and no evidence has been reported in the aged human spinal cord. Aged dogs were used to examine the distribution of VIP immunopositivity in the sacral spinal cord. Immunocytochemistry of VIP and alpha-synuclein were also examined in the aged human spinal cord. The VIP immunopositivity in aged dog was reconfirmed our previous finding illustrated by immunofluorescent study. Megalogneurite was also identified by nitric oxide synthase (NOS) immunoreaction in aged dog. The VIP positive megaloneurites both in age dog and human were detected in dorsal root entry zoon, Lissauers tract, dorsal commissural nucleus and anterior commissural gray as well as in the lateral funiculus of the sacral spinal cord exclusive of other segments of spinal cord. Alpha-synuclein positivity was present mini-aggregation and Lewy body in the sacral spinal cord of aged human, that also occurred in the lumber, thoracic and cervical spinal cord. It was firstly tested that VIP megaloneurites occurred in the aged human sacral spinal cord, especially in the white matter. Megaloneurites identified by NADPH-d-VIP-NOS immunoreaction could implicate for the dysfunction of pelvic organs in the aged human being.

neuroscience↗

bioRxiv2019

Neurofeedback linked suppression of subthalamic beta oscillations speeds up movement initialisation in Parkinsonian Patients

Enhanced beta oscillations (13-30 Hz) in the subthalamic nucleus (STN) have been associated with clinical impairment in Parkinsons disease (PD), such as rigidity and slowing of movement, with the suppression of STN beta activity through medication or deep brain stimulation correlating with improvement in these symptoms. Recent studies have also emphasized the importance of the time dynamics of the STN beta oscillations in the pathology of PD. An increased probability of prolonged beta bursts, defined as periods when beta band power exceeds a certain threshold, was more closely related to motor symptoms than average power; and the occurrence of beta bursts just before a go cue slows cued movements. Here we adopted a sequential neurofeedback-behaviour task paradigm to investigate whether patients with PD can learn to suppress pathological beta oscillations recorded from STN with neurofeedback training and whether the training improves the motor performance. Results from twelve patients showed that, compared with the control condition, the neurofeedback training led to reduced incidence and duration of beta bursts in the STN local field potential (LFP) and also reduced the synchrony between the STN LFP and cortical activities measured through EEG in the beta frequency band. The changes were accompanied by a reduced reaction time in cued movements. These results suggest that volitional suppression of beta bursts facilitated by neurofeedback training could help improve movement initialisation in Parkinsons disease.\n\nSignificance StatementOur study suggests that a neurofeedback paradigm which focuses on the time dynamics of the target neural signal can facilitate volitional suppression of pathological beta oscillations in the STN in Parkinsons disease. Neurofeedback training was accompanied by reduced reaction time in cued movements, but associated with increased tremor in tremulous patients. The results strengthen the link between subthalamic beta oscillations and motor impairment, and also suggest that different symptom-specific neural signals could be targeted to improve neuromodulation strategies, either through brain stimulation or neurofeedback training, for patients with tremor and bradykinesia-rigidity.

neuroscience↗

bioRxiv2019

New mechanism-based inhibitors of aspartate transcarbamoylase for anticancer drug development

Aspartate transcarbamoylase (ATCase) is a key enzyme which regulates and catalyzes the second step of de novo pyrimidine synthesis in all organisms. E. coli ATCase is a prototypic enzyme regulated by both product feedback and substrate cooperativity, whereas human ATCase is a potential anticancer target. Through structural and biochemical analyses, we revealed that R167/130s loop region in ATCase serves as a gatekeeper for the active site, playing a new and unappreciated role in feedback regulation. Based on virtual compound screening simultaneously targeting the new regulatory region and active site of human ATCase, two compounds were identified to exhibit strong inhibition of ATCase activity, proliferation of multiple cancer cell lines, and growth of xenograft tumors. Our work has not only revealed a previously unknown regulatory region of ATCase that helps explain feedback regulation, but also successfully guided the identification of new ATCase inhibitors for anticancer drug development using a dual-targeting strategy.

cancer biology↗

bioRxiv2019

Specialized NADPH diaphorase membrane-related localizations in the brainstem of the pigeons (Columba livia)

NADPH diaphorase (N-d) is used to a histochemical identification of subgroup of neuronal cells. Beside regular intracellular N-d positivity, membrane-related positivity revealed as a specialized staining pattern in the pigeon brain stem. In the investigation of the nervous system of homing pigeons (Columba livia) with N-d staining, we found a specialized structure, which temporally was termed as N-d tubular glomerular body/structure or as T-J body related to the last name of authors. This N-d positive specialization constituted by tubular components bilaterally located in the medial to the lemniscus spinalis in the medulla oblongata. The tubular components were moderate staining. T-J body was a longitudinal oriented structure of 2400 m with N-d staining. N-d positive tubular components were twisted and intermingled together. Beside the young adult pigeons, T-J body s were also consistently detected in the aged pigeons. Membrane-related staining were also detected in the other rostral nuclei in the brain stem. With discussion and review of related scientific literatures, T-J body was considered as a new anatomical structure or a new feature of the existent nucleus. In summary, beside N-d intracellular distribution, there were other three N-d membrane-related localizations: mini-aggregation, patch-aggregation, and arrangement along tubular unit.

neuroscience↗

bioRxiv2019

A comparative assessment of aging-related NADPH diaphorase positivity in the spinal cord and medullary oblongata between pigeon and murine

NADPH diaphorase (N-d) positive neurons has been examined in many animals. N-d neurodegenerative neurites were detected in some animal models. However, detailed information of N-d positivity and aging related changes was still lack in the spinal cord and medulla oblongata of pigeons. In this study, we evaluated the N-d positivity and aging alterations in the spinal cord and medullary oblongata of the pigeon compared with rat and mouse. In pigeons, N-d neurons were more numerous in the dorsal horn, around the central canal and in the column of Terni in the thoracic and lumbar segments and scattered neurons occurred in the ventral horn of spinal segments. N-d neurons also occurred in the white matter of spinal cord. Morphometrical analysis demonstrated in the lumbosacral, cervical and thoracic regions. Compared with young pigeons, the size of N-d soma was significantly altered in aged pigeons. Meanwhile, the dramatic morphological changes occurred in the lumbar to sacral segments. The most important findings of this study were aging-related N-d positive bodies (ANB) in aged pigeons, mainly in the nucleus cuneatus externus (CuE), occasionally in the nuclei gracilis et cuneatus. ANBs were identified in the gracile nuclei in spinal cord in the aged rats and mice. ANBs were also detected in the CuE spinal nucleus in the aged rats. Immunohistochemistry also showed that the aging changes occurred in the cell types and neuropeptides in aged animals. The results suggested the weak inflammation and neuronal dysfunction in the spinal cord in aged pigeons. Our results suggested that the ANB could be considered as aging marker in the central nervous system.

neuroscience↗

bioRxiv2019

Transcriptome Profile Analysis of Twisted Leaf Disease Response in Susceptible Sugarcane with Narenga porphyrocoma Genetic Background

Sugarcane is an important industrial crop with a high sugar yield that has become a leading energy crop worldwide. It is widely cultivated in tropical and subtropical regions. Various diseases beset the cultivation of sugarcane. The molecular study of disease resistance in sugarcane is limited by its complicated genome. In our study, RNA-seq was employed to detect the mechanism of twisted leaf disease tolerance in modern cultivar sugarcane, which derived from Narenga porphyrocoma. We completed high-throughput transcriptomic sequencing of 12 samples, including three stages of a susceptible (NSBC1_T \"H3-8\") and an unsusceptible cultivar (NSBC1_CK \"H-19\") with two biological repeats, respectively. Using the Saccharum spontaneum genome as reference, the average mapping ratio of the clean data was over 70%. Among the differentially expressed genes between H3-8 and H3-19, we focused on the analysis of hormone pathways and resistance (R) genes. The results showed that twisted leaf disease triggers hormone networks and around 40% of R genes conditioned lower expression in the susceptible cultivar. One of the possible reasons for H3-8 being susceptible to twisted leaf disease might be the null/retarded response of R genes, especially in pre-onset stage (46% down-regulated) of pathogens infection.

genomics↗

bioRxiv2019

Identification of a functional non-coding variant in the GABAA receptor α2 subunit of the C57BL/6J mouse reference genome: Major implications for neuroscience research

GABA type-A (GABA-A) receptors containing the 2 subunit (Gabra2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the GABRA2 locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. Gabra2 expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of Gabra2 brain mRNA and protein in the B6J strain relative to other inbred strains, and identify and validate the causal mutation in B6J. The mutation is a single base pair intronic deletion located adjacent to a splice acceptor site that only occurs in the B6J reference genome. The deletion became fixed in B6J between 1976 and 1991 and is now pervasive in many engineered lines, BXD strains generated after 1991, the Collaborative Cross, and the majority of consomic lines. Repair of the deletion using CRISPR-Cas9 mediated gene editing on a B6J genetic background completely restored brain levels of Gabra2 mRNA and protein. Comparison of transcript expression in hippocampus, cortex, and striatum between B6J and repaired genotypes revealed alterations in GABA-A receptor subunit expression, especially in striatum. These results suggest that naturally occurring variation in GABRA2 levels between B6J and other substrains or inbred strains may also explain strain differences in anxiety-like or alcohol and drug response traits related to striatal function. Characterization of the B6J private mutation in the Gabra2 gene is of critical importance to molecular genetic studies in neurobiological research as this strain is widely used to generate genetically engineered mice and murine genetic populations, and is the most widely utilized strain for evaluation of anxiety-like, depression-like, pain, epilepsy, and drug response traits that may be partly modulated by Gabra2 function.

genetics↗

bioRxiv2019

Dual forms of aging-related NADPH diaphorase neurodegeneration in the sacral spinal cord of aged non-human primates

We discovered two different anomalous NADPH diaphorase (NADPH-d) positive alterations, which were expressed as aging-related NADPH-d positive spheroidal bodies and megaloneurites specially distributed in the superficial dorsal horn, dorsal gray commissure (DGC), lateral collateral pathway (LCP) and sacral parasympathetic nucleus (SPN) in the aged monkeys sacral spinal cord, compared with the cervical, thoracic and lumbar segments. In the gracile nucleus of aged monkeys, only aging-related spheroidal bodies were observed and no megaloneurites occurred. The dense, abnormal NADPH-d positive megaloneurites, extremely different from regular NADPH-d positive fibers, were prominent in the sacral segments and occurred in extending from Lissauers tract (LT) through lamina I along the lateral boundary of the dorsal horn to the region of the SPN. Meanwhile, large diameter punctate NADPH-d activity occurred and scattered in the lateral white matter of the LCP and dorsal root entry zone (DREZ) at the same level of NADPH-d abnormality in the gray matters. Those dot-like NADPH-d alterations were examined by horizontal sectioning and indicated ascending or descending oriental fibers. These NADPH-d megaloneurites had the same composition as the punctate NADPH-d alterations and were co-localized with the VIP immunoreaction, while the ANBs did not coexist with the VIP immunoreaction. Both ANBs and megaloneurites provide consistent evidence that the anomalous neuritic alterations in the aged sacral spinal cord are referred to as a specialized aging marker in the pelvic visceral organs in non-human primates.

neuroscience↗

bioRxiv2019

Unbinding Kinetics and Multiple Pathways of p38 MAPK Inhibitors

Rational Drug Discovery still faces a major hurdle for the prediction of drug efficacy in vivo solely based on its binding affinity for the target in vitro. The traditional perspective has clearly proven to be inadequate as it lacks the consideration of essential aspects such as pharmacokinetics and binding kinetics in determining drug efficacy as well as toxicity. Residence time, the average lifetime of drug-target complex, has undoubtedly gained broader recognition as a better predictor for lead optimization. Long residence time can lead to sustained pharmacological effect and may also mitigate off-target toxicity. To showcase the importance of drug-target binding kinetics and unravel the underlining mechanism for variation of residence time, unbinding kinetics of two distinct type II inhibitors of p38 MAP kinase were for the first time investigated and compared by molecular dynamics and metadynamics simulation approaches. Free energy landscape of key motions associated with unbinding process was constructed for inhibitors with different unbinding rates. Multiple unbinding pathways and rebinding were revealed during the drug-target dissociation process of faster unbinder Lig3 and slower unbinder Lig8 respectively, suggesting a novel mechanism of unbinding kinetics. The comparative studies imply the hydrophobic and Hydrogen-bonding interaction in the R1 group of ligands is crucial for the slow unbinding. Such kind of computational approaches could also be applied to predict unbinding pathways and kinetics of many other drugs, and facilitate the design of efficient kinase inhibitors.

pharmacology and toxicology↗