Search

Fragment-based drug discovery (FBDD) has emerged as a powerful strategy to confront the challenges faced by conventional drug development approaches, particularly in the context of central nervous system (CNS) disorders. FBDD involves the screening of libraries that comprise thousands of small molecular fragments, each no greater than 300 Da in size. Unlike the generally larger molecules from high-throughput screening that limit customisation, fragments offer a more strategic starting point. These fragments are inherently compact, providing a strong foundation with good binding affinity for the development of drug candidates. The minimal elaboration required to transition the hit into a drug-like molecule is not only accelerated, but also it allows for precise modifications to enhance both their activity and pharmacokinetic properties. This shift towards a fragment-centric approach has seen commercial success and holds considerable promise in the continued streamlining of the drug discovery and development process. In this review, we highlight how FBDD can be integrated into the CNS drug discovery process to enhance the exploration of a target. Furthermore, we provide recent examples where FBDD has been an integral component in CNS drug discovery programs, enabling the improvement of pharmacokinetic properties that have previously proven challenging. The FBDD optimisation process provides a systematic approach to explore this vast chemical space, facilitating the discovery and design of compounds piece by piece that are capable of modulating crucial CNS targets.

Background: Immediate implant placement (IIP) or Type I implants have become more attractive than conventional implant placements as it reduces the number of surgical procedures and allows faster delivery of the final restoration compared to conventional implant placements. However, the survival of Type I implants varies depending on multiple factors. Purpose: To evaluate the survival rate of Type I implants, and to describe the factors influencing their failure. Materials and methods: A developed search strategy was applied to identify randomised controlled trials on single-unit immediate implants including at least six human participants with a minimum follow-up time of 12 months and published between 1 January 1999 and 1 January 2020 in several databases. The data were extracted independently using validated data extraction forms. Information on survival rates, number of implants placed, loading protocols, setting of the study, location of implants in the jaw, antibiotic protocol, grafting methods, and implant geometry were obtained and assessed. Results: Twenty-six randomised controlled trials with an average follow-up time of 24 months (range = 12–120 months) were included and analysed to give a survival rate ranging between 83.7 and 100%. Fifteen studies reported implant failures, of which twelve reported early losses (loss before definitive restoration). Nine early losses were due to lack of osseointegration, two did not report the reason for implant failure, and one was reported as iatrogenic. Of the eleven studies with 100% survival rates, the common trend observed was the use of titanium implants and an antibiotic regimen using amoxicillin. Conclusions: The survival rate for immediate single implant placement ranged from 83.7 to 100%. Implant failure was not consistently reported and when reported, failure due to lack of osseointegration prior to placement of the definitive restoration was the most common descriptor. Other attributed reasons included infection abscess, mobility after immediate loading, and iatrogenic complications.

Summary: Mutated Ras and Raf kinases are well-known to promote cancer metastasis via flux through the Ras/Raf/MEK/ERK (mitogen-activated protein kinase [MAPK]) pathway. A role for non-mutated Raf in metastasis is also emerging, but the key mechanisms remain unclear. Elevated expression of any of the three wild-type Raf family members (C, A, or B) can drive metastasis. We utilized an in vivo model to show that wild-type C-Raf overexpression can promote metastasis of immortalized prostate cells in a gene dosage-dependent manner. Analysis of the transcriptomic and phosphoproteomic landscape indicated that C-Raf-driven metastasis is accompanied by upregulated MAPK signaling. Use of C-Raf mutants demonstrated that the dimerization domain, but not its kinase activity, is essential for metastasis. Endogenous Raf monomer knockouts revealed that C-Raf’s ability to form dimers with endogenous Raf molecules is important for promoting metastasis. These data identify wild-type C-Raf heterodimer signaling as a potential target for treating metastatic disease.