ASD2023: towards the integrating landscapes of allosteric knowledgebase.

Allosteric regulation, induced by perturbations at an allosteric site topographically distinct from the orthosteric site, is one of the most direct and efficient ways to fine-tune macromolecular function. The Allosteric Database (ASD; accessible online at http://mdl.shsmu.edu.cn/ASD) has been systematically developed since 2009 to provide comprehensive information on allosteric regulation. In recent years, allostery has seen sustained growth and wide-ranging applications in life sciences, from basic research to new therapeutics development, while also elucidating emerging obstacles across allosteric research stages. To overcome these challenges and maintain high-quality data center services, novel features were curated in the ASD2023 update: (i) 66 589 potential allosteric sites, covering > 80% of the human proteome and constituting the human allosteric pocketome; (ii) 748 allosteric protein-protein interaction (PPI) modulators with clear mechanisms, aiding protein machine studies and PPI-targeted drug discovery; (iii) 'Allosteric Hit-to-Lead,' a pioneering dataset providing panoramic views from 87 well-defined allosteric hits to 6565 leads and (iv) 456 dualsteric modulators for exploring the simultaneous regulation of allosteric and orthosteric sites. Meanwhile, ASD2023 maintains a significant growth of foundational allosteric data. Based on these efforts, the allosteric knowledgebase is progressively evolving towards an integrated landscape, facilitating advancements in allosteric target identification, mechanistic exploration and drug discovery.

Designing drugs and chemical probes with the dualsteric approach.

Traditionally, drugs are monovalent, targeting only one site on the protein surface. This includes orthosteric and allosteric drugs, which bind the protein at orthosteric and allosteric sites, respectively. Orthosteric drugs are good in potency, whereas allosteric drugs have better selectivity and are solutions to classically undruggable targets. However, it would be difficult to simultaneously reach high potency and selectivity when targeting only one site. Also, both kinds of monovalent drugs suffer from mutation-caused drug resistance. To overcome these obstacles, dualsteric modulators have been proposed in the past twenty years. Compared to orthosteric or allosteric drugs, dualsteric modulators are bivalent (or bitopic) with two pharmacophores. Each of the two pharmacophores bind the protein at the orthosteric and an allosteric site, which could bring the modulator with special properties beyond monovalent drugs. In this study, we comprehensively review the current development of dualsteric modulators. Our main effort reason and illustrate the aims to apply the dualsteric approach, including a "double win" of potency and selectivity, overcoming mutation-caused drug resistance, developments of function-biased modulators, and design of partial agonists. Moreover, the strengths of the dualsteric technique also led to its application outside pharmacy, including the design of highly sensitive fluorescent tracers and usage as molecular rulers. Besides, we also introduced drug targets, designing strategies, and validation methods of dualsteric modulators. Finally, we detail the conclusions and perspectives.

Deciphering the comprehensive knowledgebase landscape featuring infertility with IDDB Xtra.

Infertility affects ∼15% of couples globally and half of cases are related to genetic disorders. Despite growing data and unprecedented improvements in high-throughput sequencing technologies, accumulated fertility-related issues concerning genetic diagnosis and potential treatment are urgent to be solved. However, there is a lack of comprehensive platforms that characterise various infertility-related records to provide research applications for exploring infertility in-depth and genetic counselling of infertility couple. To solve this problem, we provide IDDB Xtra by further integrating phenotypic manifestations, genomic datasets, epigenetics, modulators in collaboration with numerous interactive tools into our previous infertility database, IDDB. IDDB Xtra houses manually-curated 2369 genes of human and nine model organisms, 273 chromosomal abnormalities, 884 phenotypes, 60 genomic datasets, 464 epigenetic records, 1144 modulators relevant to infertility diagnosis and treatment. Additionally, IDDB Xtra incorporated customized graphical applications for researchers and clinicians to decipher in-depth disease mechanisms from the perspectives of developmental atlas, mutation effects, and clinical manifestations. Users can browse genes across developmental stages of human and mouse, filter candidate genes, mine potential variants and retrieve infertility biomedical network in an intuitive web interface. In summary, IDDB Xtra not only captures valuable research and data, but also provides useful applications to facilitate the genetic counselling and drug discovery of infertility. IDDB Xtra is freely available at https://mdl.shsmu.edu.cn/IDDB/and http://www.allostery.net/IDDB.

Photo-induced synthesis of ß-sulfonyl imides from carboxylic acids.

A photo-induced imidation process of carboxylic acids is described. Numerous carboxylic acids could convert to ß-sulfonyl imides in the presence of N-sulfonyl ynamides under visible light irradiation. Control experiments and mechanistic studies demonstrate that this imidation process involves a hydroacyloxylation/radical rearrangement cascade. This protocol represents a direct imidation method from carboxylic acids under mild conditions, with broad scope and high atom-economy.

Tanshinones: An Update in the Medicinal Chemistry in Recent 5 Years.

Tanshinones are an important type of natural products isolated from Salvia miltiorrhiza Bunge with various bioactivities. Tanshinone IIa, cryptotanshinone and tanshinone I are three kinds of tanshinones which have been widely investigated. Particularly, sodium tanshinone IIa sulfonate is a water-soluble derivative of tanshinone IIa and it is used in clinical in China for treating cardiovascular diseases. In recent years, there are increasing interests in the investigation of tanshinones derivatives in various diseases. This article presents a review of the anti-atherosclerotic effects, cardioprotective effects, anticancer activities, antibacterial activities and antiviral activities of tanshinones and structural modification work in recent years.

Dynamics of Post-Translational Modification Inspires Drug Design in the Kinase Family.

Post-translational modification (PTM) on protein plays important roles in the regulation of cellular function and disease pathogenesis. The systematic analysis of PTM dynamics presents great opportunities to enlarge the target space by PTM allosteric regulation. Here, we presented a framework by integrating the sequence, structural topology, and particular dynamics features to characterize the functional context and druggabilities of PTMs in the well-known kinase family. The machine learning models with these biophysical features could successfully predict PTMs. On the other hand, PTMs were identified to be significantly enriched in the reported allosteric pockets and the allosteric potential of PTM pockets were thus proposed through these biophysical features. In the end, the covalent inhibitor DC-Srci-6668 targeting the PTM pocket in c-Src kinase was identified, which inhibited the phosphorylation and locked c-Src in the inactive state. Our findings represent a crucial step toward PTM-inspired drug design in the kinase family.