AREA COVERED: The authors explore the literature to compile the success stories of AI-driven drug candidates that are currently being assessed in clinical trials or have investigational new drug (IND) status. The authors also provide the reader with their expert perspectives for future developments and their opinions on the field.
EXPERT OPINION: Partnerships between AI companies and the pharma industry are booming. The early signs of the impact of AI on DDD are encouraging, and the pharma industry is hoping for breakthroughs. AI can be a promising technology to unveil the greatest successes, but it has yet to be proven as AI is still at the embryonic stage.
AREA COVERED: The presented review article mainly summarizes the developments of small molecule KRAS inhibitors as drug candidates and rational approaches that are being utilized for the selective targeting of KRAS signaling in the mutant cancer cells.
EXPERT OPINION: After the initial success in targeting the mutant KRAS G12C variants, the search has been shifted to address the challenges concerning the resistance and efficacy of small molecule KRAS inhibitors. However, the contribution of other KRAS mutations at G12V, G13C, and G13D variants causing cancers is much higher than the mutations at G12C. In view of this aspect, specific attention is required to target all other mutations as well. Accordingly, for the development of KRAS targeted therapies, the design of small molecule inhibitors that can inhibit KRAS signaling and as well as target inhibition of other signaling pathways like RAS-SOS and RAS-PI3K has to be explored extensively.
AREAS COVERED: Herein, the authors discuss the various factors that contribute to the quality of studies using animal models based on the evaluation of studies published in 2022. The factors affecting the quality of studies using animal models, such as the animal species, age, and sex, are discussed, along with various methods and outcomes of studies involving different animal models of glaucoma.
EXPERT OPINION: Translating animal research data to clinical applications remains challenging. Our observations in this review clearly indicate that many studies lack scientific robustness not only in their experiment conduct but also in data analysis, interpretation, and presentation. In this context, ensuring the internal validity of animal studies is the first step in quality assurance. External validity, however, is more challenging, and steps should be taken to satisfy external validity at least to some extent.
RESEARCH DESIGN AND METHODS: The present work examines the frequency, distribution, prevalence, and diversity of nitrogen atoms in a dataset comprising 2,049 small molecules approved by different regulatory agencies (FDA and others). Various types of nitrogen atoms, such as sp3-, sp2-, sp-hybridized, planar, ring, and non-ring are included in this investigation.
RESULTS: The results unveil both previously reported and newly discovered patterns of nitrogen atom distribution around the center of mass in the majority of drug molecules.
CONCLUSIONS: This study has highlighted intriguing trends in the role of nitrogen atoms in drug design and development. The majority of drugs contain 1-3 nitrogen atoms within 5Å from the center of mass (COM) of a molecule, with a higher preference for the ring and planar nitrogen atoms. The results offer invaluable guidance for the multiparameter optimization process, thus significantly contributing toward the conversion of lead compounds into potential drug candidates.
RESEARCH DESIGN AND METHODS: A dataset comprising 4359 thrombin inhibitors is used to scrutinize various categories of nitrogen atoms such as ring, non-ring, aromatic, and non-aromatic. In addition, selected aromatic and aliphatic N-heterocycles have been analyzed.
RESULTS: The analysis indicates that ~62% of thrombin inhibitors possess five or fewer nitrogen atoms. Substituted N-heterocycles have a high occurrence, like pyrrolidine (23.24%), pyridine (20.56%), piperidine (16.10%), thiazole (9.61%), imidazole (7.36%), etc. in thrombin inhibitors.
CONCLUSIONS: The majority of active thrombin inhibitors contain nitrogen atoms close to 5 and a combination of N-heterocycles like pyrrolidine, pyridine, piperidine, etc. This analysis provides crucial insights to optimize the transformation of lead compounds into potential anti-thrombin inhibitors.