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1.
Sci Total Environ ; 931: 172523, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38657804

RESUMO

Landscape features can impede dispersal, gene flow, and population demography, resulting in the formation of several meta-populations within a continuous landscape. Understanding a species' ability to overcome these barriers is critical for predicting genetic connectivity and population persistence, and implementing effective conservation strategies. In the present study, we conducted a fine-scale spatial genetic analysis to understand the contemporary gene flow within red panda populations in the Eastern Himalayas. Employing geometric aspects of reserve design, we delineated the critical core habitats for red pandas, which comprise 14.5 % of the landscape (12,189.75 Km2), with only a mere 443 Km2 falling within the protected areas. We identified corridors among the core habitats, which may be vital for the species' long-term genetic viability. Furthermore, we identified substantial landscape barriers, including Sela Pass in the western region, Siang river in the central region, and the Dibang river, Lohit river, along with Dihang, Dipher, and Kumjawng passes in the eastern region, which hinder gene flow. We suggest managing red panda populations through the creation of Community Conservation Reserves in the identified core habitats, following landscape-level management planning based on the core principles of geometric reserve design. This includes a specific emphasis on identified core habitats of red panda (CH-RP 5 and CH-RP 8) to facilitate corridors and implement meta-population dynamics. We propose the development of a comprehensive, long-term conservation and management plan for red pandas in the transboundary landscape, covering China, Nepal, and Bhutan.

3.
Mol Biol Rep ; 51(1): 136, 2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38236328

RESUMO

BACKGROUND: Captive breeding programs play a vital role in conservation of threatened species, necessitating an understanding of genetic diversity among captive individuals to ensure long-term genetic viability, appropriate mate selection, and successful reintroduction to native habitats. METHODS AND RESULTS: We did not observe any recent genetic bottleneck, and population showed moderate genetic diversity. The estimated effective population size, representing individuals capable of contributing genetically to future generations, was estimated as 18.6 individuals (11.4-35.1 at 95% CI). Based on the genetic make-up and allelic diversity, we found seventeen pangolins (11 females and 6 males) were genetically unrelated and relatively more potent than others. CONCLUSION: In this study, we evaluated the captive breeding program of the Indian pangolin population at the Pangolin Conservation Breeding Centre in Nandankanan Zoological Park, Bhubaneswar, Odisha. We highlight the significance of genetic monitoring within the captive population of Indian pangolin for preserving genetic diversity and ensuring the long-term survival of the species. We established the genetic profiles of all 29 pangolins and identified 17 pangolins to be prioritized for enhanced breeding and future zoo exchange programs. We appreciate the zoo authorities for promoting genetic assessment of pangolin for better and more effective monitoring of the captive breeding of the endangered Indian pangolin.


Assuntos
Cruzamento , Pangolins , Humanos , Feminino , Masculino , Animais , Alelos , Espécies em Perigo de Extinção , Perfil Genético
5.
Sci Rep ; 13(1): 18152, 2023 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-37875501

RESUMO

The trans-Himalayan region of India, although have xeric features, still supports a unique assemblage of biodiversity, including some of the charismatic and endemic species. In the present study, we studied blue sheep (Pseudois nayaur) across the distribution range in the Western trans Himalayas of India and found about 18,775 km2 area suitable for blue sheep. The explicit Bayesian based spatial and non-spatial population structure analysis assigned blue sheep into two genetic populations, i.e., Ladakh and Lahaul-Spiti. We found relatively high genetic divergence in blue sheep which is also supported by the low current flow in Circuitscape model. With the multiple evidences, we explain landscape resistance facilitated by the landscape heterogeneity, and large patches of unsuitable habitats forced population divergence and poor functional connectivity. We found that blue sheep population has been demographically stable in the past, but showed a slight decline within the last few decades. This study is the first range-wide attempt to exhibit landscape features in shaping the spatial distribution, genetic structure and demography patterns of blue sheep in Western Himalayas, and will be of use in the conservation and management planning of blue sheep.


Assuntos
Ecossistema , Genética Populacional , Animais , Ovinos/genética , Teorema de Bayes , Biodiversidade , Deriva Genética
6.
Environ Monit Assess ; 195(11): 1386, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37889333

RESUMO

It is becoming more widely recognised that free-ranging dogs, which have a nearly global distribution, threatening native wildlife. Their increasing population and spread to new areas is of growing concern for the long-term viability of wildlife species. Hence, it is imperative to understand the factors responsible for their infestation and map areas where native species are most vulnerable. Using the random forests algorithm, we modelled the free-ranging dog infestation in the Trans-Himalayan region to pinpoint the high-risk areas where free-ranging dogs are threatening the native wildlife species. We found that the likelihood of free-ranging dog occurrence is most in valley regions and up to 4000 m, often in proximity to roads. Our results also indicated that free-ranging dog prefers areas with wildlife near to protected areas. The predictor variables, such as potential evapotranspiration of the coldest quarter, distance to protected areas, elevation, distance to roads, and potential evapotranspiration of the driest quarter, significantly influence the distribution of the free-ranging dogs. We found that within the Ladakh region of the Trans-Himalayan area, the high-risk zones for free-ranging dogs are located in and around Hemis National Park, Karakoram Wildlife Sanctuary, and Changthang Wildlife Sanctuary. While, in the Lahaul and Spiti region the high-risk areas encompass Pin Valley National Park, Inderkilla National Park, Khirganga National Park, Kugti Wildlife Sanctuary, and several other protected areas. We identified the potentially high-risk areas for implementing strategies to mitigate the possible impact of free-ranging dogs on native wildlife of the Himalayas. Hence, the identified high priority areas can be used for implementing actions for controlling the population growth and further preventing the infestation of the free-ranging dogs into the new areas.


Assuntos
Animais Selvagens , Monitoramento Ambiental , Animais , Cães , Meio Ambiente , Parques Recreativos
7.
Biology (Basel) ; 12(8)2023 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-37626983

RESUMO

Pleistocene glaciations had profound impact on the spatial distribution and genetic makeup of species in temperate ecosystems. While the glacial period trapped several species into glacial refugia and caused abrupt decline in large populations, the interglacial period facilitated population growth and range expansion leading to allopatric speciation. Here, we analyzed 40 genomes of four species of ibex and found that Himalayan ibex in the Pamir Mountains evolved independently after splitting from its main range about 0.1 mya following the Pleistocene species pump concept. Demographic trajectories showed Himalayan ibex experienced two historic bottlenecks, one each c. 0.8-0.5 mya and c. 50-30 kya, with an intermediate large population expansion c. 0.2-0.16 mya coinciding with Mid-Pleistocene Transitions. We substantiate with multi-dimensional evidence that Himalayan ibex is an evolutionary distinct phylogenetic species of Siberian ibex which need to be prioritized as Capra himalayensis for taxonomic revision and conservation planning at a regional and global scale.

8.
Environ Sci Pollut Res Int ; 30(34): 82895-82905, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37335516

RESUMO

The Kashmir musk deer (Moschus cupreus, hereafter KMD) is one of the top conservation priority species which is facing population decline due to poaching, habitat loss, and climate change. Therefore, the long-term survival and viability of KMD populations in their natural habitat require conservation and management of suitable habitats. Hence, the present study attempted to assess the suitable habitat of KMD in three protected areas (PAs) of the Western Himalayan region of Uttarakhand using the Maxent modelling algorithm. Our results suggest that Kedarnath wildlife sanctuary (KWLS) possesses the maximum highly suitable habitats (22.55%) of KMD, followed by Govind Pashu Vihar National Park & Sanctuary (GPVNP&S; 8.33%) and Gangotri National Park (GNP; 5%). Among the environmental variables, altitude was the major contributing factor governing the distribution of KMD in KWLS. In contrast, human footprint in GPVNP&S and precipitation in GNP were the major contributing factors governing the distribution of KMD in these respective PAs. The response curve indicated that habitats with less disturbance falling in the altitudinal zone of 2000-4000 m were the most suitable habitat range for the distribution of KMD in all three PAs. However, in the case of GNP suitable habitat of KMD increases with an increase in the value of variables bio_13 (precipitation of wettest month). Further, based on our results, we believe that the predictors of suitable habitat change are site specific and cannot be generalized in the entire distribution range of the species. Therefore, the present study will be helpful in making proper habitat management actions at fine scale for the conservation of KMD.


Assuntos
Cervos , Animais , Humanos , Ecossistema , Ruminantes , Animais Selvagens , Índia
9.
Biology (Basel) ; 12(6)2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37372071

RESUMO

Insufficient research has been conducted on musk deer species across their distribution range, primarily because of their elusive behaviour and the fact they occupy remote high-altitude habitats in the Himalayas above 2500 m. The available distribution records, primarily derived from ecological studies with limited photographic and indirect evidence, fail to provide comprehensive information on the species distribution. Consequently, uncertainties arise when attempting to determine the presence of specific taxonomic units of musk deer in the Western Himalayas. This lack of knowledge hampers species-oriented conservation efforts, as there need to be more species-specific initiatives focused on monitoring, protecting, and combatting the illegal poaching of musk deer for their valuable musk pods. We used transect surveys (220 trails), camera traps (255 cameras), non-invasive DNA sampling (40 samples), and geospatial modelling (279 occurrence records) to resolve the taxonomic ambiguity, and identify the suitable habitat of musk deer (Moschus spp.) in Uttarkashi District of Uttarakhand and the Lahaul-Pangi landscape of Himachal Pradesh. All the captured images and DNA-based identification results confirmed the presence of only Kashmir musk deer (KDM) (Moschus cupreus) in Uttarakhand and Himachal Pradesh. The results suggest that KMD inhabit a narrow range of suitable habitats (6.9%) of the entire Western Himalayas. Since all evidence indicates that only KMD are present in the Western Himalayas, we suggest that the presence of other species of musk deer (Alpine musk deer and Himalayan musk deer) was wrongly reported. Therefore, future conservation plans and management strategies must focus only on KMD in the Western Himalayas.

10.
Biology (Basel) ; 12(3)2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36979074

RESUMO

Wildlife corridors that connect mosaic habitats in heterogeneous mountainous landscapes can be of high significance as they facilitate the genetic and demographic stability of free-ranging populations. Peripheral populations of widespread species are usually ignored in conservation planning. However, these populations retain locally common alleles and are genetic reservoir under the changing climatic conditions. Capra sibirica has widespread distribution, and its southern peripheral population is distributed in the Indian trans-Himalayan region (ITR). In the present study, we studied the spatial distribution and genetic make-up of Himalayan ibex from the ITR following the landscape genetics approach. We obtained 16 haplotypes at the mitochondrial d-loop region and found a stable demography in the past with a recent decline. With 10 nuclear microsatellites, we ascertained 111 unique individuals assigned into two clusters following Bayesian and non-Bayesian clustering analysis with several admixed individuals. We also recorded 25 first-generation migrants that reflected relatively high dispersal and gene-flow across the range. We identified a 19,835 sq.km suitable area with 13,311 sq.km in Ladakh and 6524 sq.km in Lahaul-Spiti. We identified a novel movement corridor for Himalayan ibex across the Lahaul-Zanskar-Sham valley (L-Z-SV) that displayed a fairly good conductance with low genetic divergence among the samples collected on the L-Z-SV corridor. We propose declaring a protected area in the Lahaul and Kargil districts to prioritize dedicated conservation efforts for the Himalayan ibex and other sympatric ungulates that impart a major role in the diet of large carnivore and balancing ecosystem services in the trans-Himalayan region.

11.
Sci Total Environ ; 867: 161349, 2023 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-36621499

RESUMO

The improvement and application of pest models to predict yield losses is still a challenge for the scientific community. However, pest models were targeted chiefly towards scheduling scouting or pesticide applications to deal with pest infestation. Thysanoptera (thrips) significantly impact the productivity of many economically important crops worldwide. Until now, no comprehensive study is available on the global distribution of pest thrips, as well as on the extent of cropland vulnerability worldwide. Further, nothing is known about the climate change impacts on these insects. Thus the present study was designed to map the global distribution and quantify the extent of cropland vulnerability in the present and future climate scenarios using data of identified pest thrips within the genus, i.e., Thrips, Frankliniella, and Scirtothrips. Our found significant niche contraction under the climate change scenarios and thrips may reside primarily in their thermal tolerance thresholds. About 3,98,160 km2 of cropland globally was found to be affected in the present scenario. However, it may significantly reduce to 5530 Km2 by 2050 and 1990 km2 by 2070. Further, the thrips distribution mostly getting restricted to Eastern North America, the North-western of the Indian sub-continent, and the north of Europe. Among all realms, thrips may lose ground in the Indo-Malayan realm at the most and get restricted to only 27 out of 825 terrestrial ecoregions. The agrarian communities of the infested regions may get benefit if these pests get wiped out, but on the contrary, we may lose species diversity. Moreover, the vacated niche may attract other invasive species, which may seriously impact the species composition and agricultural productivity. The present study findings can be used in making informed decisions about prioritizing future economic and research investments on the thrips in light of anticipated climate change impacts.


Assuntos
Agricultura , Mudança Climática , Tisanópteros , Animais , Produtos Agrícolas , Controle de Pragas/tendências
12.
Sci Rep ; 12(1): 17602, 2022 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-36266303

RESUMO

Species with sympatric distribution influence ecosystem dynamics and are impacted by the presence of other co-existing species. Assessing the coexistence and the role of interspecific interactions with the landscape variables is necessary to know the species co-occurrence in space. In the Indian Himalayan region, such studies are completely lacking due to limited efforts being made, mainly because of complex terrains and inaccessible landscape features. We used camera trapping and sign survey in a multi-species occupancy framework to understand the influence of environmental variables on occupancy and detection probability of species-specific and pair-wise interaction of the three ungulates in Uttarkashi. Our results concluded that individual species' occupancy probabilities were related both to the environmental variables and the presence or absence of other interacting species. Our top model showed evidence of interspecific interaction among species pairs, and the occupancy probability of species one varied in the presence or absence of another species. The overall activity patterns were similar among all the three species and were found active throughout the day. The activity overlap between sambar-barking deer (Dhat1 value = 0.85) was considerably higher than barking deer-goral (Dhat1 value = 0.78). The findings of the present study will be useful for the conservation and management of ungulates in the Indian Himalayan and adjoining regions.


Assuntos
Cervos , Ecossistema , Animais , Simpatria , Especificidade da Espécie , Probabilidade
13.
Sci Total Environ ; 853: 158679, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36099955

RESUMO

Large forested landscapes often harbour significant amount of biodiversity and support mankind by rendering various livelihood opportunities and ecosystem services. Their periodic assessment for health and ecological integrity is essential for timely mitigation of any negative impact of human use due to over harvesting of natural resources or unsustainable developmental activities. In this context, monitoring of mega fauna may provide reasonable insights about the connectivity and quality of forested habitats. In the present study, we conducted a largest non-invasive genetic survey to explore mammalian diversity and genetically characterized 13 mammals from the Indian Himalayan Region (IHR). We analyzed 4806 faecal samples using 103 autosomal microsatellites and with three mitochondrial genes, we identified 37 species of mammal. We observed low to moderate level of genetic variability and most species exhibited stable demographic history. We estimated an unbiased population genetic account (PGAunbias) for 13 species that may be monitored after a fixed time interval to understand species performance in response to the landscape changes. The present study has been evident to show pragmatic permeability with the representative sampling in the IHR in order to facilitate the development of species-oriented conservation and management programmes.


Assuntos
Conservação dos Recursos Naturais , Ecossistema , Animais , Humanos , Biodiversidade , Mamíferos/genética
14.
Ecol Evol ; 12(7): e9120, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35866011

RESUMO

Brown bear-mediated conflicts have caused immense economic loss to the local people living across the distribution range. In India, limited knowledge is available on the Himalayan brown bear (HBB), making human-brown bear conflict (HBC) mitigation more challenging. In this study, we studied HBC in the Lahaul valley using a semi-structured questionnaire survey by interviewing 398 respondents from 37 villages. About 64.8% of respondents reported conflict in two major groups-crop damage (30.6%) and livestock depredations (6.2%), while 28% reported both. Conflict incidences were relatively high in summer and frequently occurred in areas closer to the forest (<500 m) and between the elevations range of 2700 m to 3000 m above sea level (asl). The dependency of locals on forest resources (70%) for their livelihood makes them vulnerable to HBC. The "upper lower" class respondents were most impacted among the various socioeconomic classes. Two of the four clusters were identified as HBC hot spots in Lahaul valley using SaTscan analysis. We also obtained high HBC in cluster II with a 14.35 km radius. We found that anthropogenic food provisioning for HBB, livestock grazing in bear habitats, and poor knowledge of animal behavior among the communities were the major causes of HBC. We suggest horticulture crop waste management, controlled and supervised grazing, ecotourism, the constitution of community watch groups, and others to mitigate HBC. We also recommend notifying a few HBB abundant sites in the valley as protected areas for the long-term viability of the HBB in the landscape.

15.
PLoS One ; 17(7): e0271556, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35862366

RESUMO

The snow leopard (Panthera uncia) plays a vital role in maintaining the integrity of the high mountain ecosystem by regulating prey populations and maintaining plant community structure. Therefore, it is necessary to understand the role of the snow leopard and its interaction with prey species. Further, elucidating landscape use and co-occurrence of snow leopard and its prey species can be used to assess the differential use of habitat, allowing them to coexist. We used camera trapping and sign survey to study the interactions of snow leopard and its prey species (Siberian Ibex- Capra sibrica and Blue sheep-Pseudois nayaur) in the Spiti valley Himachal Pradesh. Using the occupancy modelling, we examined whether these prey and predator species occur together more or less frequently than would be expected by chance. To understand this, we have used ten covariates considering the ecology of the studied species. Our results suggest habitat covariates, such as LULC16 (barren area), LULC10 (grassland), ASP (aspect), SLP (slope) and DW (distance to water), are important drivers of habitat use for the snow leopard as well as its prey species. Furthermore, we found that the snow leopard detection probability was high if the site was used by its prey species, i.e., ibex and blue sheep. Whereas, in the case of the prey species, the probability of detection was low when the predator (snow leopard) was present and detected. Besides this, our results suggested that both species were less likely to detect together than expected if they were independent (Snow leopard-Ibex, Delta = 0.29, and snow leopard-blue sheep, Delta = 0.28, both the values are <1, i.e., avoidance). Moreover, despite the predation pressure, the differential anti-predation habitat selection and restriction of temporal activities by the prey species when snow leopard is present allows them to co-exist. Therefore, considering the strong link between the habitat use by the snow leopard and its prey species, it is imperative to generate quantitative long-term data on predator-prey densities and the population dynamics of its prey species in the landscape.


Assuntos
Panthera , Animais , Conservação dos Recursos Naturais , Ecologia , Ecossistema , Panthera/fisiologia , Comportamento Predatório , Ovinos
16.
Mol Biol Rep ; 49(5): 4107-4114, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35359235

RESUMO

BACKGROUND: Genetics driven interventions if adopted in conservation breeding projects may enhance the overall success by prioritizing breeding among genetically most competent individuals and delaying or completely diminishing the ill effects of inbreeding. METHODS AND RESULTS: In the present study, we investigated genetic make-up of 15 tigers housed at five different captive facilities of West Bengal in India and report the moderate level of genetic variation. We identified five tigers based on individual genetic attributes that may be prioritized for future breeding or animal exchange programmes. The occurrence of first and second order related individuals in captivity require management attention and they should be paired considering their immediate genetic background. CONCLUSION: Considering tiger as a case study, we highlight the use of genetic assessment and necessity to validate the studbook records in formulating adaptive management strategies for long-term conservation and management of species of interest.


Assuntos
Tigres , Animais , Conservação dos Recursos Naturais/métodos , DNA , Patrimônio Genético , Variação Genética , Endogamia , Tigres/genética
17.
Sci Total Environ ; 826: 154081, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35218816

RESUMO

Trachypithecus geei Khajuria, 1956 or Golden langur are an endangered colobine primate species that are distributed in the transboundary region of Bhutan and India. The species is severely threatened because of increasing habitat fragmentation and isolation across its entire range, especially the populations in Assam, India. The distribution range of the species has not been updated for the last two decades, nor is there any proper evaluation of the habitat requirements for the species. Therefore, we mapped the habitat suitability for the species across its entire distribution and projected its habitat suitability on the simulated landscape for the future (2031). The results indicate that out of the total range extent (66,320 km2), only 12,265 km2 (18.49%) is suitable for the species at present, which will further be reduced to 8884 km2 by the year 2031, indicating major range contraction. These suitable habitats are largely scattered and fragmented in southern range of the species. Among the predictors used, the distance to evergreen and deciduous broadleaf forest was the strongest predictor out of the 35 used for model building. Moreover, land use and land cover were found to be more informative than the climatic variables. Much of the suitable habitats of the species are located outside the protected area network in the landscape. Therefore, we identified landscape configurations and suitable habitat areas for the future conservation and monitoring of Golden Langur in the protected areas of its range.


Assuntos
Presbytini , Animais , Conservação dos Recursos Naturais , Ecossistema , Espécies em Perigo de Extinção , Florestas , Primatas
18.
Mol Biol Rep ; 49(2): 1573-1579, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34729672

RESUMO

BACKGROUND: The common leopard (Panthera pardus fusca), which persists in most of its historic range, is experiencing steady population decline due to habitat loss, anthrophonic disturbances, illegal poaching for their body parts, and retaliatory killings in response to the leopard-human conflicts. METHODS AND RESULTS: We analysed 143 scats samples and identified 32 unique leopards following a selected panel of seven loci with cumulative PID sibs 5.30E-04. We observed moderate genetic diversity at nuclear (Ho = 0.600 ± 0.06) and mitochondrial markers (Hd = 0.569 ± 0.009; π = 0.001 ± 0.0002) and found sub-structuring in the leopard population at Uttarkashi, Western Himalayas. CONCLUSIONS: The present study exhibits the utility of non-invasive genetics in monitoring the leopard population and paves the path to investigate population genetic parameters in further studies.


Assuntos
Conservação dos Recursos Naturais/métodos , Genética Populacional/métodos , Panthera/genética , Animais , Ásia , Crime/tendências , Ecossistema , Fezes/química , Variação Genética/genética
19.
Mol Biol Rep ; 49(1): 811-816, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34668102

RESUMO

BACKGROUND: The sambar (Rusa unicolor) is one of the largest deer distributed across diverse habitats of India and threatened due to habitat loss, changes in the land-use patterns, illegal poaching, and anthropogenic disturbances. Here, we report the first population genetics account of sambar deer from the Western Himalayas. METHODS AND RESULTS: We observed relatively compromised genetic diversity (π = 0.0008 ± 0.0006 at mtDNA and Ho = 0.499 ± 0.056 at nDNA). We identified 60 unique individuals using a select panel of seven loci (PID sib cum 1.60E-03). Bayesian skyline plot showed a stable demographic history since the past 8 kyr with a decline in recent years. The population lacked genetic structuring, likely due to the contiguous distribution and large dispersal patterns of sambar. CONCLUSION: The preliminary findings are valuable in exploring the utility of genetic diversity in monitoring the sambar population, estimating density following capture-recapture analysis, and aid to the conservation planning of sambar in large landscapes.


Assuntos
DNA Mitocondrial/genética , Cervos/genética , Genética Populacional/métodos , Polimorfismo Genético , Animais , Efeitos Antropogênicos , Teorema de Bayes , DNA Mitocondrial/isolamento & purificação , Ecossistema , Fezes/química , Loci Gênicos , Genótipo , Índia , Repetições de Microssatélites/genética
20.
Bioorg Med Chem ; 52: 116504, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34814071

RESUMO

Pantothenate kinase (PANK) is the critical regulator of intracellular levels of coenzyme A and has emerged as an attractive target for treating neurological and metabolic disorders. This report describes the optimization, synthesis, and full structure-activity relationships of a new chemical series of pantothenate competitive PANK inhibitors. Potent drug-like molecules were obtained by optimizing a high throughput screening hit, using lipophilic ligand efficiency (LipE) derived from human PANK3 IC50 values to guide ligand development. X-ray crystal structures of PANK3 with index inhibitors from the optimization were determined to rationalize the emerging structure activity relationships. The analysis revealed a key bidentate hydrogen bonding interaction between pyridazine and R306' as a major contributor to the LipE gain observed in the optimization. A tractable series of PANK3 modulators with nanomolar potency, excellent LipE values, desirable physicochemical properties, and a well-defined structural binding mode was produced from this study.


Assuntos
Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Piridazinas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Ligação de Hidrogênio , Ligantes , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade
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