Julolaelaps Berlese in Republic of Korea. Females and males of a new species, Julolaelapsgigassp. nov., were collected on a captive giant African millipede, Archispirostreptusgigas (Spirostreptida: Spirostreptidae). The new species is described and illustrated based on morphological characters of the adult females and males and compared with known congeners. This new species is the first record of Julolaelaps from Republic of Korea. In addition, an updated key to all known species of the genus is presented.This paper reports on a new species of mite of the genus  Mesostigmata and Sarcoptiformes  (Polydesmida (Diplopoda)  , but somplopoda)  and one plopoda) . The genplopoda) . Howeverplopoda) .Julolaelaps was first established by Iphiopsididae. It was subsequently included in the Laelapidae-Hypoaspidinae by Vitzthum (1942: 763) and in the Laelapidae-Iphiopsidinae by Julolaelaps as a separate genus of the family Laelapidae Canestrini, 1891, subfamily Iphiopsidinae Kramer, 1886.Laelapidae associated with insects and soil from the Republic of Korea  (Spirostreptida: Spirostreptidae) in Republic of Korea. In addition, an update of the key of Julolaelaps species is presented to include the new species.Several authors have already recorded a collection of of Korea . The prer4, respectively. Length and width of the sternal shield were measured at the maximum length and broadest points, respectively. The length of the epigynal shield was measured along the midline from the anterior margin of the hyaline extension to the posterior margin of the shield, and its maximal widthwas measured posterior to genital setae st5. Leg length was measured from the base of the coxa to the apex of the tarsus (excluding the pre-tarsus). The nomenclature used for the dorsal idiosomal chaetotaxy follows that of The millipedes were purchased for exhibition purposes and kept in a plastic cage with a sufficient amount of corroded oak sawdust. Mites were removed from the captive giant African millipede using a fine brush, cleared in lactic acid solution and mounted in PVA medium . The linTaxon classificationAnimaliaMesostigmataLaelapidaeGenusBerlese74184677-0EB4-50DB-B065-565362759728JulolaelapsJulolaelapsdispar Berlese, 1916, by original designation. Berlese, 1916: 31. Type species Hypoaspis (Julolaelaps) . – Ryke, 1959: 7.Julolaelaps used here is based on that of The concept of Taxon classificationAnimaliaMesostigmataLaelapidaeEA0D6D37-B974-56BE-9137-8746BB42DFB4https://zoobank.org/FDD68D96-90DF-4196-9DD5-377DCF03D633Holotype. Republic of Korea • ♀; Sangju, Silkworm and Insect Management Center; 36°57'N, 128°15'E; 19 May 2020; S. Keum leg.; on captive giant African millipede, Archispirostreptusgigas (Spirostreptida: Spirostreptidae); NIBRIV 0000905722. Paratypes. Republic of Korea • 2♀ 2♂; same data as for holotype; NIBRIV 0000905723, NIBRIV 0000905724, NIBRIV 0000905725, NIBRIV 0000905726.Z5 conspicuously longer than other setae on shield, podonotal and opisthonotal parts of dorsal shield slightly hypotrichous, setae in z- and s/S-series displaced laterally (on soft cuticle) and some missing ; posterior margin of shield somewhat truncated; dorsal shield reduced, not covering entire idiosoma, opisthogastric and lateral soft cuticle with 37 pairs of setae, including 23 pairs of r-R-UR setae. Sternal shield reduced, bearing only st1 and st2, eroded posteriorly, st3 and metasternal setae (st4) inserted on unsclerotized cuticle, epigynal shield drop-shaped, parapodal plates broadly thickened, extending behind coxae IV, endopodal plates III/IV broadly thickened, peritreme relatively long and rather broad, extending to anterior level of coxa II, cheliceral fixed digit with 2–3 teeth. Chaetotaxy of legs normal for free-living Laelapidae, except tibia III with nine setae  and genu IV with 10 setae . Male with separate sternogenital and anal shields, chelicerae with edentate digits including a regressed fixed digit and a stylet-like movable digit bordered by a very long spermatodactyl.Dorsal shield smooth, without reticulation, bearing 22 pairs of minute acicular setae, setae Female (N = 3). Figs Dorsal idiosoma , nine pairs of opisthonotal setae, plus 21 pairs of setae on lateral soft cuticle (including S1-5 and R1-7); Zx, unpaired or asymmetrical setae and z1, z6, J3 absent, setae similar in length (9–15) and thicknesses; clonal setae Z5 (26–31) longer than other setae on shield. Muscle insertions prominent as desclerotised circular patches. Dorsal shield with 22 pairs of discernible pore-like structures, including only five pairs of gland openings  and 17 pairs of poroids. Shape, position and relative length and thicknesses of setae shown in Figs oma Figs , 12. LenVentral idiosoma ], and two pairs of poroids , eroded posteriorly, surface without reticulate ornamentation, smooth, st3 (30–32) and metasternal setae  inserted on soft integument, metasternal poroids (iv3) apparently absent  and length (228–235), anterior and posterior margins rounded, with some irregular longitudinal and oblique lines, otherwise relatively smooth, bearing a pair of simple setae st5 (20–23) inserted on lateral margins of shield, near level of posterior edge of coxae IV; paragenital poroids iv5 located on soft cuticle lateral to shield near seta st5 , setae more or less same in length (18–24) and thickness  > h1 = h2 (18–21) > h3 (14–16) , genu 2-2/1, 2/1-1 , tibia: 2-1/1, 2/1-2. Leg IV , femur 1-2/1, 1/0-1 , genu 2-2/1, 3/0-2, tibia 2-1/1, 3/1-2. Tarsi II-IV with 18 setae ; with some ventral and lateral setae thickened. All pretarsi with well-developed paired claws, rounded pulvilli and normal ambulacral stalk.gs. Figs . Legs IIg I Fig. : coxa 0-g I Fig. : coxa 0-g I Fig. : coxa 0- IV Fig. : coxa 0-Male (N = 2). Figs Dorsal idiosoma. Length 760–768, width 525–530. Dorsal shield length 647–653, width 345–350; ornamentation and chaetotaxy as in female.Ventral idiosoma.  (19–30), and two pairs of poroids; anal shield free, length 117–123, width 93–98, surface without reticulate ornamentation, smooth, post-anal seta (25–28) slightly longer than para-anals (18–23), cribrum well developed, with 3–4 irregular rows of spicules, each extending from cribrum to near base of post-anal setae; anal opening located at anterior level of shield; pair of glands gv3 inserted on shield lateral margins, at level para-anal setae .The name of this species refers to its occurrence on giant African millipede of the species Julolaelaps because of its conspicuously reduced sternal shield, bearing only two pairs of sternal setae , eroded posteriorly and endopodal plates III/IV broadly thickened. In other features the new species is closest to J.vandaelensis Maes, 1983 in having a genital shield narrower than anal shield, peritreme almost reaching anterior margin of coxae II and dorsal shield with 22 pairs of setae. It is distinguished from this species by the uniform minute acicular dorsal setae and the reduced dorsal shield, not covering entire idiosoma, leaving an unsclerotised cuticle surrounding the dorsal shield.The female of the new species is unique within Laelapidae based on phylogenetic evidence, merging the genera associated with millipedes , elevating the subfamily (Iphiopsidinae) to the level of the family (Iphiopsididae). According to av2 on tibia I, see pl2 on genu IV, see Iphiopsididae as a separate family from Laelapidae. Based on attributes #58 and #62, the placement of the new species (Julolaelapsgigas) in Iphiopsididae cannot be considered due to the presence of both setae av2 and pl2 on tibia I and genu IV, respectively.Julolaelapsgigas sp. nov. requires some changes to the diagnosis they introduced for each species group. Here we combine them into two species groups and call them simply as follows: dispar and gigas species groups. The dispar group includes species with largely complete dorsal setae complement, with more than 29 setae pairs (at least series J and Z complete), while the gigas species group is characterized by reduced dorsal setae, with at most 25 setae pairs (at least series J and/or Z incomplete). Julolaelapsbuensis Maes, 1983 was not included in the key because the dorsal of the idiosoma is not described due to poor fixation   : J.celesJulolaelapsgigas were discovered on captive giant African millipedes. The mystery remains regarding how these mites came to inhabit this particular species. We need to do experiments to understand the real ecological role of these mites, regardless of where they came from.The millipede from which the mites were collected was obtained from a pet market where the import and breeding of exotic animals flourish as a business. The second author observed that the millipede was mite-free when it got to the Silkworm and Insect Management Center  for an exhibition. Nonetheless, all specimens of


Most AEs were low-grade, although 19.21% of AEs were common terminology criteria for adverse events (CTCAE) Grades 3 or 4. A large spectrum of skin AEs was documented during treatment of advanced melanoma, and distinct phenotypes were observed, depending on treatment classes. AEs occurred earlier during treatment with TT than with ICB, and distinct types of skin AEs were associated with respective treatment classes. This study comprehensively describes skin AEs occurring during systemic treatment for melanoma at a single center.Recent progress in the treatment of advanced melanoma has led to the improved survival of affected patients. However, novel treatments also lead to considerable and distinct skin toxicity. To further characterize cutaneous adverse events (AE) of systemic treatments, we conducted a single-center retrospective study of biopsy-proven cutaneous adverse events of melanoma treatment over a period of 10 years at the University Hospital of Zurich, Switzerland. In 102 identified patients, 135 individual skin AEs developed. Immune checkpoint blockade (ICB) was causal for 81 skin AEs, and 54 were related to targeted therapies (TT). Recorded types of skin AEs included lichenoid, maculopapular, acneiform, urticarial, panniculitis, folliculitis, psoriasiform, granulomatous, eczematous, and others. The incidence of skin AEs was higher with TT (18.54%) than with ICB (9.64%,  The incidence of malignant melanoma, the most lethal type of skin cancer, has rapidly increased in the past few decades ,2. With Until 2010, chemotherapy with dacarbazine was the standard of care for patients with metastatic melanoma; however, the objective response rate (ORR) was limited ,4. Today, the backbone of advanced melanoma treatment consists of two approaches: immune checkpoint blockade (ICB) and targeted therapy (TT). Currently approved immunotherapy regimens for melanoma from the adjuvant setting to metastatic disease target immune checkpoints, such as cytotoxic T-lymphocyte antigen 4 , programmed cell death protein receptor 1 , its ligand PD-L1 , and lymphocyte-activation gene 3 . Specifically, CTLA-4 is expressed on T-cells, where it competes with CD28 for the binding of CD80/CD86, thereby dampening the second signal and reducing early T-cell activation. On the other hand, PD-1 is expressed on activated T-cells; its ligand PD-L1 (as well as its second ligand PD-L2) is expressed both on myeloid cells and certain tumor cells, amongst others. The binding of PD-1 leads to inhibition of the T-cell and can ultimately lead to apoptosis of the previously activated T-cell. Lastly, LAG-3 also is an inhibitory receptor expressed on T-cells; its binding to MHC Class II decreases T-cell activity. It supports chronic T-cell exhaustion. A further role has been suggested in the suppressive function of regulatory T-cells. In healthy systems, these checkpoints prevent damage to healthy tissue from autoimmune disease. Whereas CTLA-4 regulates the initial phase of a T-cell response, PD-1 dampens the activity of effector T-cells. This dampening prevents melanoma from circumventing the endogenous immune system by inhibiting a repressor of immune activation . AdditioTargeted therapy, on the other hand, is based on aberrant signaling in the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) pathway. Between 40 and 60% of melanomas harbor a targetable mutation in the gene BRAF, e.g., BRAF V600E ,9. Both However, these novel treatment options, whilst improving patients’ survival, are frequently associated with distinct toxicities. In particular, cutaneous toxicity is amongst the most frequent adverse events in systemic melanoma treatment ,11,12. WParticularly well-described skin AEs of melanoma treatments include lichenoid immune-related cutaneous adverse events (ircAE), associated with PD-1/PD-L1 blockade , as wellThe side effect profiles of BRAF- and MEK-inhibitors differ in frequency depending on the regimen. The most commonly reported AEs with BRAF inhibitors are cutaneous toxicities , fatigue, and arthralgia . With MEWhilst certain adverse events, such as lichenoid ircAE in PD-1-based ICB and acneiform rashes with TT, tend to be found consistently, the reported incidence of specific phenotypes varies widely between studies. Furthermore, most skin AEs of melanoma treatment reported in the literature are not biopsy-proven. Thus, to achieve a comprehensive and systematic characterization of all biopsy-proven skin AEs occurring due to melanoma treatments at a large comprehensive cancer center, we here report a single-center retrospective analysis of the last 10 years at the University Hospital of Zurich.In this retrospective analysis, we identified 135 individual skin AEs documented in 102 patients between January 2012 and December 2021. A sole skin AE occurred in 81 patients; 15 patients experienced two skin AEs; three patients with three skin AEs; and one patient each developed four, five, and six skin AEs, respectively. The average age at the timepoint of the development of the skin AE was 60.3 years (32.3–92.4 years). Seventy (69%) patients were male; 32 (31%) patients were female  were categorized as lichenoid, 42 (31.11%) as maculopapular, eight (5.93%) as acneiform, seven (5.19%) as urticarial, seven (5.19%) as panniculitis, seven (5.19%) as folliculitis, five (3.7%) as psoriasiform, three (2.22%) as granulomatous, three (2.22%) eczematous, and six (4.44%) others. The latter includes bullous (2), not classified (2), transient acantholytic dermatosis  (1), and pityriasis rubra pilaris (1) b. n = 81) included 35 (43.20%) pembrolizumab, 18 (22.22%) nivolumab, 17 (20.99%) combined ipilimumab and nivolumab, six (7.41%) ipilumumab, three (3.70%) spartalizumab, and two (2.47%) atezolizumab. Attributions to targeted therapies (n = 54) included 17 (31.48%) vemurafenib and cobimetinib, 16 (29.63%) dabrafenib and trametinib, five (9.26%) each of encorafenib and binimetinib, and binimetinib monotherapy, four (7.41%) of vemurafenib monotherapy, one (1.85%) case each of trametinib and of encorafenib, as well as five (9.25%) other tyrosine kinase inhibitors such as imatinib, naporafenib, and lenvatinib.Out of the 135 skin AEs, 81 (60%) were attributed to immunotherapies, and 54 (40%) to targeted therapies a. ICB ren = 498, 9.64%) due to immunotherapies and 28  due to targeted therapies. Overall, patients treated with TT developed significantly more skin AEs (p = 0.0029).Between 2018 and 2021, 498 courses of immunotherapy regimens were administered, as well as 151 courses of targeted therapies. Immunotherapies included 175 courses of combined CTLA-4 and PD-1 blockade, with 323 courses of anti-PD-1 monotherapy. TT included one course of BRAF inhibition alone and 150 courses of combined BRAF- and MEK inhibition. During this time, 76 biopsy-proven skin AEs were recorded, including 48 (p = 0.0091)  than with ICB  . Compari 0.0091) . Howeverp = 0.0116). Most (89.36%) lichenoid rashes were attributed to ICB; when comparing incidences, lichenoid skin AEs occur more frequently (4.42%) during ICB than during TT . However, this trend is not statistically significant. Biopsy-proven maculopapular rash occurred more frequently with TT (61.90%) than with ICB (38.10%). This frequency translates to an incidence of 9.93% with TT and 2.83% with ICB (p = 0.0010). Comparing immunotherapy regimens’ causality for lichenoid AEs, the incidence with PD-1 monotherapy (5.06%) was higher compared to combinations with CTLA-4 blockade (3.03%). However, this observation did not reach statistical significance (p = 0.356). Acneiform rashes were strongly associated with TT . When comparing incidences, it was higher (2.65%) with TT than with ICB . All Grade 4 AEs led to treatment discontinuation and required treatment with systemic corticosteroids. Out of 23 Grade 3 AEs, four (17.39%) cases led to permanent discontinuation of the cancer treatment causing the skin AE. Additionally, combined ipilimumab and nivolumab was resumed as nivolumab monotherapy due to the G3 AE in one (4.35%) case. Furthermore, in six (26.09%) cases, treatment was interrupted or discontinued due to other adverse events, progression of disease, or other causes unrelated to the skin AE. In two (8.70%) G3 skin AEs, treatment was temporarily interrupted for improved management. Overall, 13 (56.52%) cases of G3 skin AE were maintained on active treatment, accompanied by appropriate management that included systemic corticosteroids or semi-occlusive high-potency topical corticosteroids. Of note, Grade 1 and 2 skin AEs did not lead to treatment interruptions and were successfully managed with topical corticosteroids or calcineurin inhibitors. Additionally, a subset of acneiform rashes was managed with oral tetracyclines in addition to topical corticosteroids. Overall, 45 (33.82%) AEs were of CTCAE Grade 1, 64 (47.06%) of Grade 2, 23 (16.91%) of Grade 3, and three (2.21%) of Grade 4. The latter included two severe MPR and one lichenoid AE overlapping with Stevens–Johnson syndrome, the latter associated with nivolumab, the two others with TT. High-grade skin AEs (CTCAE Grades 3 and 4) were infrequent and more strongly associated with TT than with ICB  of the University Hospital of Zurich, for pathology reports of skin AEs reported between 1 January 2012 and 31 December 2021.The following key words have been used for the search within the ‘Dermapro’ histopathology database: “ipilimumab”, nivolumab”, “pembroli-zumab”, “vemurafenib”, “cobimetinib”, “dabrafenib”, “trametinib”, “encorafenib”, “binimetinib”, “check*”, “Anti-PD-1”, “MEK*”, and “BRAF-Inhibitor” for the medications and “lichen*” or “maculopapular,” along with “drug reaction” and “rash”, along with “immunotherapy” for the type of skin AE. In our study, we included skin AEs from patients with diagnosed MM, treated with immunotherapy or targeted therapies as mentioned above. In addition, patients receiving new therapies such as atezolizumab or spartalizumab developing skin AEs were also included in our analysis. Ensuring comprehensive documentation, only patients treated at the University Hospital of Zurich were included, and a high likelihood of a causal relationship between melanoma treatment and rash, as assessed by both the treating dermatologist and the investigators , was additionally required. Causality and the type of skin AE were determined mirroring clinical decisionmaking. The history and clinical presentation were integrated with the histopathological information to determine the type of skin AE as well as causal relationship by assessing the exposure to incriminated cancer drugs and by ruling out differential diagnoses. Cutaneous AEs associated with tebentafusp—a novel bispecific fusion protein—were not included, as tebentafusp is directly targeting melanocytes; therefore, skin inflammation is an expected on-target effect and wanted in this treatment approach. Hence, tebentafusp-associated cutaneous events were excluded. In addition, vitiligo-like depigmentation and alopecia were not considered for this investigation. Vitiligo-like depigmentations have previously been described , and aloThe CTCAE scale was used to grade the severity of skin AEs. Grade 0 would be no adverse event, and Grade 5 would be death due to the adverse event, with mild (Grade 1) impairing of activities of daily life (ADL), medical intervention required (Grade 2), hospitalization required (Grade 3), and life threatening (Grade 4) in between. For cutaneous AE, when no additional information regarding complicating factors, e.g., impairment of ADL, is available, Grade 1 is less than 10% body surface area (BSA) affected; Grade 2 is 10–30% BSA; and Grade 3 will be more than 30% BSA .For approximate incidence calculations, internal registry data for systemic treatment of melanoma (part of the multi-center Eumelareg registry) collected between January 2018 and December 2021 were used. p-values < 0.05 were considered statistically significant.The data were collected, and descriptive statistics were computed using Microsoft Excel . Additional statistical analyses were conducted using Prism ; In this single-center review of skin AEs during 10 years of systemic treatment for advanced melanoma, we identified 135 individual, biopsy-proven events of skin AE in 102 patients. The most frequent types of skin AE were lichenoid and maculopapular rashes. Overall, targeted therapies were associated with a higher incidence of skin AEs, including high-grade skin AEs. Furthermore, rashes occurred earlier in patients treated with TT. Acneiform but also maculopapular rashes were mostly associated with targeted therapies, whereas lichenoid rashes were mostly attributed to ICB.Overall incidences of rashes due to immunotherapy of 13.4–15% ,21 for aMost recorded skin AEs were mild to moderate (CTCAE Grades 1–2). Focusing on biopsy-proven AEs might have further contributed to a higher overall grade of AE than expected. However, with 26 total cases, severe (Grade 3 and 4) AEs are infrequent and include only three life-threatening Grade 4 AEs.Our findings are in line with previous reports describing a strong association of acneiform rashes with targeted therapies  as well In cohorts of ircAEs, pruritus on apparently unchanged skin is often the most frequently reported adverse event ,26,27,28Squamoproliferative conditions, in particular keratoacanthomas, are frequently reported with BRAF inhibitors . Such caA limitation of this study is its retrospective design. Whilst requiring histopathological confirmation strengthens the presented data, it introduces bias of selection for performing skin biopsies. This bias includes higher-grade rashes, persistent AEs, lesser-known AEs, and AEs of specific interest, whilst potentially underreporting shorter-lasting AEs such as urticarial and MPR. The value of this investigation is therefore in the robust characterization of biopsy-confirmed skin AEs, rather than in providing accurate incidences. The availability of comprehensive treatment data for comparison purposes for four years instead of the full 10 years might further limit the interpretation of incidences. However, 77 of 135 skin AEs occurred during this limited time window too, as the number of administered treatment courses increased yearly. Early and adequate management of cutaneous toxicity is crucial in order to maintain dose intensity of effective melanoma treatments whilst ensuring patients’ quality of life. Where available, guidelines or peer-reviewed recommendations, such as the EADV Task Force recommendations on managing immune-related cutaneous adverse events , should All patients undergoing systemic treatment for melanoma should be counseled on the use of fragrance-free moisturizers and the avoidance of harmful sun-exposure, as well as other skin irritations. Management of skin AE should be individualized based on the clinicopathological type in each patient.For most Grade 1 skin AEs, medium- to high-potency topical corticosteroids (limit to medium for the face) should be prescribed, with no interruption of cancer treatment. With Grade 2 AEs, topical corticosteroids (see above) are required, and the addition of a short course of oral corticosteroids  should be considered. In addition, specific approaches based on the type of skin AE are recommended. For example, phototherapy with UVBnb or specific biologics  will be preferred for psoriasiform skin AE. In the case of Grade 2 or higher pruritus, GABA analogues, such as pregabaline or gabapentine can be introduced starting at low initial doses . In acneA thorough assessment and detailed characterization of skin AEs in each patient will further enable the use of recent, targeted management approaches. As such, dupilumab, an IL4 and IL13 antibody, has recently been described as a potentially effective and safe treatment for cutaneous immune-related adverse events, including eczematous, maculopapular, and other phenotypes. Out of 39 treated patients, 34 showed at least a partial improvement of their skin AE. In addition, a significant decrease in blood eosinophils and a statistically insignificant reduction in serum IgE was noted . Other pTo identify precise incidences of subtypes of skin AEs due to treatment for advanced melanoma, pivotal trials should include a regular skin assessment by a dermatologist with precise characterization of the AE. As an alternative, a systematic prospective “real live” investigation could systematically characterize and document skin AEs prospectively in cohorts of patients treated for melanoma.Early detection and appropriate phenotypic and histological classification are essential for timely and efficacious management of skin AEs of melanoma and of cancer treatments in general ,35,36,37This single-center retrospective analysis identified skin AEs occurring during treatment for advanced melanoma. Targeted therapies showed a stronger association with skin AEs, in particular with acneiform but also maculopapular rashes as well as severe AEs. ICB led to skin AEs less frequently; lichenoid rashes were the most frequently identified subtype. Skin AEs are an important complication to this potentially life-saving treatment and need to be detected early and managed efficiently to maintain patients’ quality of life. This retrospective study investigates the characteristics and incidences of skin AEs occurring in a setting different from a prospective clinical trial. The findings should enable clinicians to better anticipate, and therefore detect and treat, skin AEs of melanoma treatments. Further prospective investigations should be undertaken to ascertain the exact incidence of skin AE types.


Altered RNA editing has been linked to several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability, in addition to depression, schizophrenia, some cancers, viral infections and autoimmune disorders. The human ADAR2 is a potential therapeutic target for managing these various disorders due to its crucial role in adenosine to inosine editing. This study applied consensus scoring to rank potential ADAR2 inhibitors after performing molecular docking with AutoDock Vina and Glide (Maestro), using a library of 35,161 compounds obtained from traditional Chinese medicine. A total of 47 compounds were predicted to be good binders of the human ADAR2 and had insignificant toxicity concerns. Molecular dynamics (MD) simulations, including the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) procedure, also emphasized the binding of the shortlisted compounds. The potential compounds had plausible binding free energies ranging from −81.304 to −1068.26 kJ/mol from the MM/PBSA calculations. ZINC000085511995, a naphthoquinone had more negative binding free energy (−1068.26 kJ/mol) than inositol hexakisphosphate (IHP) [−873.873 kJ/mol], an agonist and a strong binder of ADAR2. The potential displacement of IHP by ZINC000085511995 in the IHP binding site of ADAR2 could be explored for possible deactivation of ADAR2. Bayesian-based biological activity prediction corroborates the neuropharmacological, antineoplastic and antiviral activity of the potential lead compounds. All the potential lead compounds, except ZINC000014612330 and ZINC000013462928, were predicted to be inhibitors of various deaminases. The potential lead compounds also had probability of activity (Pa) > 0.442 and probability of inactivity (Pi) < 0.116 values for treating acute neurologic disorders, except for ZINC000085996580 and ZINC000013462928. Pursuing these compounds for their anti-ADAR2 activities holds a promising future, especially against neurological disorders, some cancers and viral infections caused by RNA viruses. Molecular interaction, hydrogen bond and per-residue decomposition analyses predicted Arg400, Arg401, Lys519, Trp687, Glu689, and Lys690 as hot-spot residues in the ADAR2 IHP binding site. Most of the top compounds were observed to have naphthoquinone, indole, furanocoumarin or benzofuran moieties. Serotonin and tryptophan, which are beneficial in digestive regulation, improving sleep cycle and mood, are indole derivatives. These chemical series may have the potential to treat neurological disorders, prion diseases, some cancers, specific viral infections, metabolic disorders and eating disorders through the disruption of ADAR2 pathways. A total of nine potential lead compounds were shortlisted as plausible modulators of ADAR2. RNA editing is a post-transcriptional process that alters RNA sequences with profound physiological consequences. The most common form of RNA editing in mammalian brain is catalyzed by the adenosine deaminases acting on RNA (ADAR) enzymes, ADAR1 and ADAR2, resulting in adenosine (A) to inosine (I) substitutions in mRNA and microRNAs, which is implicated in various diseases . By cataADAR2-mediated RNA editing activity is crucial for the nervous system functions, thus altered RNA editing has been linked to neurological disorders ,5. A fewIt has been shown that a synthetic helix-threading peptide that binds 5-HT2CR editing sites was able to selectively inhibit ADAR2 editing of 5-HT2C RNA in vitro . HoweverWhile there is an urgent need to identify inhibitors of ADAR2 that may have specificity for the RNA editing of 5-HT2CR, modifying the RNA editing of other ADAR targets may be beneficial. Epilepsy has been associated with increased RNA editing of glutamate receptors (kainate subtypes), the glutamate transporter EAAT2 (SLC1A2), CTSB, Rpa, Sparc, and OVCA2 . TherefoPrion diseases have been associated with increased RNA editing of FKRP and Rragd in mice, and may be improved by administration of ADAR inhibitor drugs. Moreover, elevated RNA editing activity has been reported as a major contributor to transcriptomic diversity in tumors , therefoThe availability of NMR and X-ray structures of the human ADAR2 (hADAR2) with the dsRNA of GluA2 offer an opportunity for the in silico screening of potential inhibitors of RNA editing ,28. ThisADAR proteins share a common structure which consists of N-terminal dsRNA binding domains (dsRBDs) and a carboxy (C)-terminal catalytic deaminase domain ,37. The Computed Atlas of Surface Topography of proteins (CASTp) predicted 52 potential binding sites, out of which only 3 were selected as plausible based on the area and volumes of the cavities . The othThe classical root mean square deviation (RMSD) was used to assess the ability of each docking tool to predict poses similar to that of the crystallographic structure. RMSD equal to or lower than 2 Å is considered good, 2 Å < RMSD < 3 Å is acceptable and RMSD > 3 Å is bad . HoweverA total of 25,131 compounds were successfully screened against the human ADAR2 protein. For each compound, AutoDock Vina generates up to nine conformers during docking. The pose or conformation with the most negative binding energy was selected as the best for each compound. The top 10% of the initial docking library (that is 2520 compounds) were shortlisted for analysis. The bound ligand, IHP had a binding energy of −8.6 kcal/mol when docked against the hADAR2. For the TCM natural products, ZINC000095913861 had the most negative binding energy when docked against the ADAR2 protein with a binding energy of −12.2 kcal/mol. ZINC000044350981 had a binding energy of −11.4 kcal/mol, while ZINC000070450936 and ZINC000070454365 both had a binding energy of −11.2 kcal/mol. Compounds ZINC000003203078, ZINC000085546044, ZINC000085593200, ZINC000085594057, and ZINC000103536976 had a binding energy of −11.1 kcal/mol.The highest binding energy was observed to be −8.9 kcal/mol among the top 10%, which is lower than the −7.0 kcal/mol threshold specified for AutoDock Vina to differentiate between putative binders and non-binders of proteins . The −7.All 37,398 TCM compounds generated via LigPrep were screened against the ADAR2 protein using Glide . For comMost of the top compounds were observed to have indole, naphthoquinone, coumarin, furanocoumarin or benzofuran moieties in their structures. Compounds including ZINC000030726422, ZINC000070450892, ZINC000070454387, ZINC000070455595, and ZINC000085492822, among others were observed to have the indole moiety. Serotonin or 5-hydroxytryptamine (5-HT) and tryptophan also have the indole moiety. Tryptophan is the only precursor of serotonin production in humans . TryptopCompounds ZINC000014690026, ZINC000070455383, ZINC000085488553, ZINC000085488571, and ZINC000085488602, among others had the benzofuran and/or coumarin moieties in their structure. Coumarins have recently been explored for treating neurological or brain disorders ,65,66,67A total of 516 compounds were observed to be in the top 10% for both AutoDock Vina and Maestro. A consensus docking score was calculated by determining the averages of the AutoDock Vina binding energy and the Glide docking score of the top compounds. The 516 compounds were then ranked based on the consensus score. The known ADAR2 binder, IHP, had a consensus score of –8.26 kcal/mol . ZINC000The study analyzed the effect of molecular weight on the binding scores. No compound with molecular weights 150 g/mol to 250 g/mol were found in the top 516 hits . It was The interaction profiles of the hADAR2 protein–ligand complexes for the shortlisted compounds were determined using Maestro. The best docking conformation from the Glide docking results were used to study the ADAR2-ligand interactions. IHP was predicted to form 12 hydrogen bonds with residues Asn391, Arg400, Arg401 (2 H-bonds), Lys519 (2 H-bonds), Ser531, Lys672, Trp687, Val688, Glu689, and Lys690 of the ADAR2 protein . It alsoZINC000095909990 formed 8 hydrogen bonds with residues Asn391, Tyr408, Met514, Arg522, Lys629, Lys662, Val688, and Pro691. It also formed pi-cation interactions with Lys629 and Lys662, and four salt bridges with Arg400, Lys519 (2), and Lys690. ZINC000095909350 had four hydrogen bond interactions with residues Asp392, Ser531, His659, and Val688; five pi-cation interactions with Arg400, Arg401, Lys519, Lys662, and Lys672; and five salt bridges with residues Arg400, Arg401, Lys519, Lys629, and Lys662. ZINC000085509666 interacted with ADAR2 via 10 hydrogen bonds with residues Asn391, Leu532, Gln529, Lys629, Tyr658, Lys662, Glu689 (3 H-bonds), and Lys690; 2 salt bridges with Lys519 and Lys690; and formed a pi-cation with Arg400.ZINC000085505346 interacted with ADAR2 via hydrogen bonds with Arg400, Arg401 (2), Trp523, Gln529, Leu532, Lys629, His659, and Trp687; pi-cation interaction with Arg522; and salt bridges with Arg522, Lys672, and Glu689. Compound ZINC000085950180 formed six hydrogen bonds with Arg401, Ser531 (2 H-bonds), Lys629, Trp687, and Asp695 and a pi-cation interaction with Lys662 . ZINC0002 methyl]-6H-[homoloba . Compounxidation . ZINC0000 μg/mL) .Isatis tinctoria [I. indigotica [Couroupita guianensis [Eupatorium laeve [50 of 0.8 μM [I. indigotica leaf extracts inhibit human hepatoma cell growth [I. indgotica and tinctoria have shown neuroprotective activities [ZINC000100513617 (indigo) is found in the leaves and seeds of both inctoria  and I. idigotica , fruits ianensis , and leaum laeve . Indigo um laeve ,198. Bisf 0.8 μM . In addil growth . Moreovetivities ,203,204,Hypoestes purpurea [Linum corymbulosum [Juniperus chinensis [50 of 992 µM [ZINC000013462928 -lign-7(E)-en-9,9′-olide) can be obtained from purpurea , Linum cmbulosum , and leahinensis . 3’,4’-bhinensis  which ishinensis ,209. Morhinensis . Also, cf 992 µM , making Some of the topmost compounds, including ZINC000085511995, ZINC000085950180, ZINC000044417732, ZINC000085850673, ZINC000085996580, and ZINC000085734971 are polyphenols. Polyphenols are known for their antioxidant ,212, antFurthermore, polyphenols can also interact with the gut microbiota ,229. SomStructure-based virtual screening (SBVS) was employed to identify potentially good ADAR2 binders with ADAR inhibitory activity . The stu6 or IHP), bound to a double-stranded ribonucleic acid (dsRNA) [The hADAR2 structure was retrieved from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) with corresponding PDB ID of 5ed2 ,239. The (dsRNA) . The dsR (dsRNA) .A total of 35,161 natural products from the Traditional Chinese Medicine (TCM) database were obtained from TCM@Taiwan, the world’s largest non-commercial TCM database, which is a catalog of ZINC15 database ,241. TheLigand structures were prepared using the Ligand Preparation Wizard (LigPrep) in Maestro. For the TCM library, a total of 37,398 compounds  were generated using LigPrep. Various ionic states, tautomeric states and stereo chemistries were generated from each input ligand molecule at a pH of 7.0 ± 2.0 using Epik . LigPrephttp://sts.bioe.uic.edu/castp/calculation.html accessed on 14 July 2022) [A literature search was conducted to identify previously reported active sites of the human ADAR2. Moreover, CASTp 3.0 (ly 2022)  was emplTwo molecular docking applications comprising Xglide (Glide Cross Docking) module in Maestro ,235 and For each docking tool, the top 10% (2520 compounds) of the total number of compounds were shortlisted after the docking process based on the docking scores. Traditional consensus scoring method was used to shortlist suitable compounds. In molecular docking, choosing compounds based on consensus scoring from a variety of docking programs produces a far higher predictive performance than using the docking scores from a single docking program . Thus, cInhibitor identification has been greatly aided by molecular docking simulations, which have allowed the prediction and investigation of potential protein–ligand interactions . However3 and the protein centered at 30.697 Å, 27.166 Å and 82.548 Å.The first step of the molecular docking run was performed using the AutoDock Vina module in PyRx (version 0.9.2) ,237. The3) and outer box sizes (26 × 26 × 26 Å3) were used for the virtual screening. Ligand vdW scale factor and cut-off for a ‘good’ RMSD were set to default . The Standard Precision (SP) algorithm was used for the molecular docking run [For the second phase of the molecular docking process, Glide Cross Docking (XGlide) was employed ,235. ForTo facilitate compound selection, the consensus scoring approach was used. A previous study had success rates of ~82% when multiple docking tools, including AutoDock , AutoDocProtein–ligand interactions help us to understand the mechanisms of ligand binding, which is crucial in drug design and development . Ligand The pharmacokinetic profiles comprising absorption, distribution, metabolism, excretion (ADME) of the shortlisted compounds were determined using SwissADME . OSIRIS Prediction of Activity Spectra of Substances (PASS) was employed to predict the biological activity of the identified compounds ,92,93. PThe unbound protein and selected ADAR2-ligand complexes were subjected to 100 ns molecular dynamics (MD) simulations using the GROningen MAchine for Chemical Simulations (GROMACS) version 5.1.5. Ligand topologies of the compounds for OPLS force field were generated using the LigParGen . Each syThe binding free energies and the other energy components including vdW, electrostatic, polar solvation and solvent accessible surface area (SASA) energies of each complex were determined using the MM/PBSA method via the g_mmpbsa tool . The ene3 and the protein centered at 40.5731 Å, 33.1458 Å and 52.5793299511 Å.The identified potential leads were finally screened against the 5-Hydroxytryptamine (or serotonin) 2C receptor (5-HT2CR) to evaluate their binding to the receptor using AutoDock Vina. The 3D structure of 5-HT2CR in complex with ritanserin was retrieved from RCSB PDB with corresponding ID 6BQH . RitanseThis study carefully predicted potential ADAR2 inhibitors which can be beneficial in the treatment of various diseases including some cancers, viral infections and neurological disorders. We employed two widely used molecular docking tools, namely AutoDock Vina and Glide  to predict the binding affinities of natural compounds from the Chinese flora and fauna. The top nine shortlisted compounds had favorable binding to the human ADAR2 and 5-HT2C receptor and were predicted to have insignificant toxicities. They also had favorable results when subjected to MD simulations and MM/PBSA calculations. One of the potential leads, ZINC000085511995, had higher binding free energy (−1068.26 kJ/mol) to the ADAR2 than the known binder, IHP (−873.873 kJ/mol), after MM/PBSA computations. The biological activity predictions and structural similarity search also corroborated the activity of the predicted compounds. The identified biomolecules can help accelerate the pace of ADAR2 research since they can be potential tools for understanding the biology of RNA editing and as a starting point for the development of potential therapeutic agents. Further experimental studies on the predicted molecules are required to determine their anti-ADAR2 activity. This study also observed the presence of naphthoquinone, indole, furanocoumarin and benzofuran moieties in most of the top compounds. Serotonin and tryptophan, which are beneficial in digestive regulation, sleep cycle and improved mood, also have the indole moiety ,49,53,55