Harnessing free energy calculations for kinome-wide selectivity in drug discovery campaigns with a Wee1 case study.

Optimizing both on-target and off-target potencies is essential for developing effective and selective small-molecule therapeutics. Free energy calculations offer rapid potency predictions, usually within hours and with experimental accuracy and thus enables efficient identification of promising compounds for synthesis, accelerating early-stage drug discovery campaigns. While free energy predictions are routinely applied to individual proteins, here, we present a free energy framework for efficiently achieving kinome-wide selectivity that led to the discovery of selective Wee1 kinase inhibitors.

MOLECULAR SURVEY OF HAEMOSPORIDIAN PARASITES IN HAWKS, FALCONS, AND OWLS (ACCIPITRIFORMES, FALCONIFORMES, STRIGIFORMES) FROM MINNESOTA AND NORTH DAKOTA, WITH REMARKS ON THE PHYLOGENETIC RELATIONSHIPS OF HAEMOSPORIDIANS IN NORTH AMERICAN RAPTORS.

Avian haemosporidians are a diverse group of apicomplexan parasites that are globally distributed and infect almost all avian orders. Haemosporidian surveys of raptors (birds of prey) are underrepresented compared to those of songbirds, perhaps because of the greater difficulty in capturing and handling raptors. In this study, we captured raptors over a 7-yr period from northeastern North Dakota and northwestern Minnesota.

Remarks on the diversity of Hysteromorpha Lutz 1931 (Digenea, Diplostomidae), with erection of a new species from South America.

Hysteromorpha Lutz, 1931 is a small but broadly distributed genus of diplostomoidean digeneans parasitic as adults primarily in cormorants, but also reported from some other fish-eating birds. Their metacercariae were found in a variety of freshwater fishes as second intermediate hosts. Prior to this study, the genus included only 3 nominal species, 2 of them distributed in the Old World and 1 in the New World.

Exploiting Solvent Exposed Salt-Bridge Interactions for the Discovery of Potent Inhibitors of SOS1 Using Free-Energy Perturbation Simulations.

Small molecules that bind the Son of Sevenless 1 protein (SOS1), thereby preventing activation of RAS, have been widely pursued as a means for cell proliferation inhibition and antitumor activity. Guided by free-energy perturbation (FEP+) simulations, we discovered that two acidic residues on the perimeter of a known small molecule binding site on SOS1, E906 and E909, constitute a potency handle that can improve inhibitor affinity by as much as 750-fold when targeted with basic groups to form salt bridges, despite being solvent exposed. Structure-Activity Relationship (SAR) and X-ray crystallographic studies demonstrate that this effect is attributable to the electrostatic interaction between the protein and ligand.

Haemosporidian infection risk and community structure determined by duck feeding guild.

Birds possess the most diverse assemblage of haemosporidian parasites, although the true diversity is unknown due to high genetic diversity and insufficient sampling across all avian clades. Waterfowl (Order Anseriformes) are an ideal group to discover hidden parasite diversity and examine the role of host ecology in parasite transmission. Waterfowl contain 2 distinct feeding guilds, dabbling and diving, which differ in niche utilization that likely alters vector encounter rates and haemosporidian parasite risk.

Enabled Discovery of KAI-11101, a Preclinical DLK Inhibitor for the Treatment of Neurodegenerative Disease and Neuronal Injury.

Dual leucine zipper kinase (DLK), expressed primarily in neuronal cells, is a regulator of neuronal degeneration in response to cellular stress from chronic disease or neuronal injury. This makes it an attractive target for the treatment of neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, and neuronal injury, such as chemotherapy-induced peripheral neuropathy. Here, we describe the discovery of a potent, selective, brain-penetrant DLK inhibitor, KAI-11101 ().

Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an Enabled Drug Discovery Platform.

Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S.

AVIAN HAEMOSPORIDIANS IN GREATER SCAUP (AYTHYA MARILA) AND LESSER SCAUP (AYTHYA AFFINIS) FROM WISCONSIN.

Avian haemosporidians are a diverse group of protozoan parasites that infect a wide range of host species. Waterfowl are an ecologically and economically important group of hosts that have been underrepresented in studies of haemosporidians. Diving ducks have unique life history traits, and morphological, behavioral, and dietary differences separate them from more common dabbling ducks.

Ubiquitin-specific protease 7 inhibitors reveal a differentiated mechanism of p53-driven anti-cancer activity.

The USP7 deubiquitinase regulates proteins involved in the cell cycle, DNA repair, and epigenetics and has been implicated in cancer progression. USP7 inhibition has been pursued for the development of anti-cancer therapies. Here, we describe the discovery of potent and specific USP7 inhibitors exemplified by FX1-5303.

Exploiting high-energy hydration sites for the discovery of potent peptide aldehyde inhibitors of the SARS-CoV-2 main protease with cellular antiviral activity.

Small-molecule antivirals that prevent the replication of the SARS-CoV-2 virus by blocking the enzymatic activity of its main protease (Mpro) are and will be a tenet of pandemic preparedness. However, the peptidic nature of such compounds often precludes the design of compounds within favorable physical property ranges, limiting cellular activity. Here we describe the discovery of peptide aldehyde Mpro inhibitors with potent enzymatic and cellular antiviral activity.

Co-infection with Leucocytozoon and Other Haemosporidian Parasites Increases with Latitude and Altitude in New World Bird Communities.

Establishing how environmental gradients and host ecology drive spatial variation in infection rates and diversity of pathogenic organisms is one of the central goals in disease ecology. Here, we identified the predictors of concomitant infection and lineage richness of blood parasites in New Word bird communities. Our multi-level Bayesian models revealed that higher latitudes and elevations played a determinant role in increasing the probability of a bird being co-infected with Leucocytozoon and other haemosporidian parasites.

Prevalence and genetic diversity of avian haemosporidian parasites in islands within a mega hydroelectric dam in the Brazilian Amazon.

The Brazilian Amazon supports an extremely diverse avifauna and serves as the diversification center for avian malaria parasites in South America. Construction of hydroelectric dams can drive biodiversity loss by creating islands incapable of sustaining the bird communities found in intact forest sites. Besides anthropogenic actions, the presence of parasites can also influence the dynamics and structure of bird communities.

Distinct biogeographic processes and areas of endemism contributed differentially to Plasmodium and Parahaemoproteus community assembly on Marajó Island.

Amazonia is the primary source of haemosporidian diversity for South American biomes. Yet, our understanding of the contribution of each area of endemism and the biogeographical processes that generated such diversity in this group of vector transmitted parasites remains incomplete. For example, a recently formed fluvial island in the Amazon delta - Marajó Island, is composed of avian lineages from adjacent Amazonian areas of endemism, but also from open habitats, such as Cerrado.

Immature hard ticks infected with Rickettsia amblyommatis on breeding birds from Pantanal.

Immature hard ticks from the genus Amblyomma feed on blood from a wide range of Neotropical avian hosts. They serve as vectors for pathogens of medical and veterinary importance, such as Rickettsia agents of the spotted fever group (SFG). Hence, determining ecological factors that increase encounter rates between immature ticks and their avian hosts may contribute to the understanding of tick-borne diseases transmission.

Haemosporidian parasites and incubation period influence plumage coloration in tanagers (Passeriformes: Thraupidae).

Birds are highly visually oriented and use plumage coloration as an important signalling trait in social communication. Hence, males and females may have different patterns of plumage coloration, a phenomenon known as sexual dichromatism. Because males tend to have more complex plumages, sexual dichromatism is usually attributed to female choice.

Host life-history traits predict haemosporidian parasite prevalence in tanagers (Aves: Thraupidae).

Vector-borne parasites are important ecological drivers influencing life-history evolution in birds by increasing host mortality or susceptibility to new diseases. Therefore, understanding why vulnerability to infection varies within a host clade is a crucial task for conservation biology and for understanding macroecological life-history patterns. Here, we studied the relationship of avian life-history traits and climate on the prevalence of and parasites.

Unravelling the diversity of the Crassiphialinae (Digenea: Diplostomidae) with molecular phylogeny and descriptions of five new species.

Crassiphialinae Sudarikov, 1960 is a large subfamily of the Diplostomidae Poirier, 1886 with a complex taxonomic history. It includes a diversity of species parasitic in the intestines of avian and mammalian definitive hosts worldwide. Dubois, 1936 is a large and broadly distributed crassiphialine genus notorious for its association with diseases in their fish second intermediate hosts.

Host foraging behavior and nest type influence prevalence of avian haemosporidian parasites in the Pantanal.

Avian haemosporidians from the genera Plasmodium and Haemoproteus are vector transmitted parasites. A growing body of evidence suggests that variation in their prevalence within avian communities is correlated with a variety of avian ecological traits. Here, we examine the relationship between infection probability and diversity of haemosporidian lineages and avian host ecological traits (average body mass, foraging stratum, migratory behavior, and nest type).

Molecular phylogeny of Diplostomum, Tylodelphys, Austrodiplostomum and Paralaria (Digenea: Diplostomidae) necessitates systematic changes and reveals a history of evolutionary host switching events.

The Diplostomidae Poirier, 1886 is a large, globally distributed family of digeneans parasitic in intestines of their definitive hosts. Diplostomum and Tylodelphys spp. are broadly distributed, commonly reported, and the most often sequenced diplostomid genera.

Loss of forest cover and host functional diversity increases prevalence of avian malaria parasites in the Atlantic Forest.

Host phylogenetic relatedness and ecological similarity are thought to contribute to parasite community assembly and infection rates. However, recent landscape level anthropogenic changes may disrupt host-parasite systems by impacting functional and phylogenetic diversity of host communities. We examined whether changes in host functional and phylogenetic diversity, forest cover, and minimum temperature influence the prevalence, diversity, and distributions of avian haemosporidian parasites (genera Haemoproteus and Plasmodium) across 18 avian communities in the Atlantic Forest.

Avian Malaria and Related Parasites from Resident and Migratory Birds in the Brazilian Atlantic Forest, with Description of a New Species.

Determining the prevalence and local transmission dynamics of parasitic organisms are necessary to understand the ability of parasites to persist in host populations and disperse across regions, yet local transmission dynamics, diversity, and distribution of haemosporidian parasites remain poorly understood. We studied the prevalence, diversity, and distributions of avian haemosporidian parasites of the genera , , and among resident and migratory birds in Serra do Mar, Brazil. Using 399 blood samples from 66 Atlantic Forest bird species, we determined the prevalence and molecular diversity of these pathogens across avian host species and described a new species of .

Mining increases the prevalence of avian haemosporidian parasites in Northeast Amazonia.

Studies contrasting parasite prevalence and host-parasite community structure between pristine and disturbed environments will improve our understanding of how deforestation affects disease transmission and parasite extinction. To determine how infection rates of a common and diverse group of avian blood parasites (Plasmodium and Haemoproteus) respond to changes in avian host composition after mining, we surveyed 25 bird communities from pristine forests (two forest types: plateau and hillside) and reforested sites in Northeast Amazonia. Infection rates and both parasite and avian host community structure exhibited considerable variation across the deforestation gradient.

Host movement and time of year influence tick parasitism in Pantanal birds.

Ticks are among the best studied parasitic groups as they spread important pathogens of medical and veterinary importance worldwide. Migratory birds can play an important role in transporting ticks infected with pathogens across wide geographic regions. It is therefore important to understand which factors promote tick parasitism rates across their avian hosts and the associated potential for disease spread.

Phylogeny and systematics of the Proterodiplostomidae Dubois, 1936 (Digenea: Diplostomoidea) reflect the complex evolutionary history of the ancient digenean group.

The Proterodiplostomidae Dubois, 1936 is a relatively small family of diplostomoidean digeneans parasitising the intestines of reptilian hosts associated with freshwater environments in tropical and subtropical regions. The greatest diversity of proterodiplostomids is found in crocodilians, although some parasitise snakes and turtles. According to the most recent revision, the Proterodiplostomidae included 17 genera within 5 subfamilies.