Expert Opinion on Drug Discovery最新文献

Introduction: Decades of research on cannabidiol (CBD) have identified thousands of purported cellular effects, and many of these have been proposed to correlate with a vast therapeutic potential. Yet despite the large volume of findings fueling broad optimism in this regard, few have translated into any demonstrable clinical benefit or even notable side effects. Therein resides the great paradox of CBD: a drug that appears to affect almost everything in vitro does not clearly do much of anything in a clinical setting.

Areas covered: Comparative critical evaluation of literature searched in PubMed and Google Scholar discovers multiple instances of inconsistent and contradictory findings regarding the pharmacology and clinical effects of CBD, as well as several uncelebrated reports that suggest potential explanations for these observations. Many of those effects attributed to the ostensible pharmacologic activity of cannabidiol are almost certainly the product of false-positive experimental results and artifactual findings that are unlikely to be realized under physiologic conditions.

Expert opinion: Concerns regarding the physiological relevance and translational potential of in vitro findings across the field of cannabinoid research are both far-reaching and demanding of attention in the form of appropriate experimental controls that remain almost universally absent.

Introduction: Antisense oligonucleotide (ASO) was established as a viable therapeutic option for genetic disorders. ASOs can target RNAs implicated in various diseases, including upregulated mRNA and pre-mRNA undergoing abnormal alternative splicing events. Therapeutic applications of ASOs have been proven with the Food and Drug Administration approval of several drugs in recent years. Earlier enzymatic stability and delivery remains a big challenge for ASOs. Introducing new chemical modifications and new formulations resolving the issues related to the nuclease stability and delivery of the ASOs. Excitingly, ASOs-based bioconjugates that target the hepatocyte have gained much attraction. Efforts are ongoing to increase the therapeutic application of the ASOs to the extrahepatic tissue as well.

Area covered: We have briefly discussed the mechanism of ASOs, the development of new chemistries, and delivery strategies for ASO-based drug discovery and development. The discussion focuses more on the already approved ASOs and those in the clinical development stage.

Expert opinion: To expand the clinical application of ASOs, continuous effort is required to develop precise delivery strategies for targeting extrahepatic tissue to minimize the off-target effects.

Introduction: Mapping the interactions between pharmaceutical compounds and their molecular targets is a fundamental aspect of drug discovery and repurposing. Drug-target interactions are important for elucidating mechanisms of action and optimizing drug efficacy and safety profiles. Several computational methods have been developed to systematically predict drug-target interactions. However, computational and experimental validation of the drug-target predictions greatly vary across the studies.

Areas covered: Through a PubMed query, a corpus comprising 3,286 articles on drug-target interaction prediction published within the past decade was covered. Natural language processing was used for automated abstract classification to study the evolution of computational methods, validation strategies and performance assessment metrics in the 3,286 articles. Additionally, a manual analysis of 259 studies that performed experimental validation of computational predictions revealed prevalent experimental protocols.

Expert opinion: Starting from 2014, there has been a noticeable increase in articles focusing on drug-target interaction prediction. Docking and regression stands out as the most commonly used techniques among computational methods, and cross-validation is frequently employed as the computational validation strategy. Testing the predictions using multiple, orthogonal validation strategies is recommended and should be reported for the specific target prediction applications. Experimental validation remains relatively rare and should be performed more routinely to evaluate biological relevance of predictions.

Background: Tuberculosis is an infectious disease that has become endemic worldwide. The causative bacteria Mycobacterium tuberculosis (Mtb) is targeted via several exciting drug targets. One newly discovered target is the Fatty Acyl-CoA synthase, which plays a significant role in activating the long-chain fatty acids.

Research design & methods: This study aims to generate novel compounds using Machine Learning (ML) algorithms to inhibit this synthase. Experimentally derived bioactive compounds were chosen from ChEMBL and used as inputs for effective molecule generation by Reinvent4. The library of new molecules generated was subjected to a two-tiered molecular docking protocol, and the results were further studied to obtain a binding free energy check.

Results: The ML-based de novo drug design (DNDD) approach successfully generated a diverse library of novel molecules targeting Fatty Acyl-CoA synthase. After rigorous molecular docking and binding free energy analysis, four new compounds were identified as potential lead candidates with promising inhibitory effects on Mtb lipid metabolism.

Conclusions: The study demonstrated the effectiveness of a machine-learning approach in generating novel drug candidates against Mtb. The identified hit compounds show potential as inhibitors of Fatty Acyl-CoA synthase, offering a new avenue for developing treatments for tuberculosis, particularly in combating drug-resistant strains.

Introduction: Hypoxia is a key feature of solid tumors, associated with aggressive behaviors such as radiation and chemotherapy resistance, increased metastasis, and poor prognosis. Hypoxia-inducible factors (HIFs) are essential transcription factors that help tumor cells adapt to hypoxic environments by promoting the expression of pro-oncogenic genes. Reducing HIF activity presents a promising strategy for advancing cancer treatment.

Area covered: In this paper, the authors present an overview of recent studies on the development of HIF-1/2 inhibitors as potential anticancer drugs. The article offers a comprehensive analysis of the structural characteristics of these inhibitors and explores their relationship with anticancer activity, focusing on research conducted over the past decade, from 2015 to 2024.

Expert opinion: Because they play a big role in medicinal chemistry and the discovery of anticancer drugs, HIF inhibitors have always gotten a lot of attention and have been used to make a lot of important molecules with different biological effects, especially in the field of cancer research. Several techniques and chemical scaffolds have successfully targeted HIF-1α. However, additional research is required to sustain HIF-1α inhibition while maintaining anticancer activity. The FDA approval of Belzutifan provided researchers with an opportunity to conduct broader HIF-2 studies.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. Treatment options and patient outcomes have not improved significantly over the past decades, increasing the need for better preclinical models. Holistic approaches that include an intact and functional immune compartment along with the patient's individual tumor microbiome will help improve the predictive value of novel drug efficacy.

Areas covered: In this review, we describe the challenges of modeling the complex and heterogeneous tumor landscape in HNSCC and the importance of sophisticated patient-specific 3D in vitro models to pave the way for clinical trials with novel immunomodulatory drugs. We also discuss the impact of the tumor microbiome and the potential implications for prospective drug screening and validation trials.

Expert opinion: The repertoire of well-characterized preclinical 3D in vitro models continues to grow. With the increasing attention to the complex cellular, immunological, molecular, and spatio-temporal characteristics of tumors, well-designed proof-of-concept studies to test novel drug efficacy are on the verge of providing valuable, practice-changing insights for clinical trials. Bringing together expertise and improving collaboration between clinicians, academics, and regulatory agencies will facilitate the translation of preclinical findings into clinically meaningful outcomes.

Introduction: Myeloproliferative neoplasms (MPNs) are rare hematopoietic disorders driven by mutations in the JAK-STAT signaling pathway genes. While JAK2 inhibitors have transformed MPN treatment, they do not eliminate the malignant clone or prevent disease progression in most patients. This limitation underscores the need for more effective therapies.

Area covered: This review examines the evolution of JAK2 inhibitors for treating MPNs. Current JAK2 inhibitors primarily function as type I inhibitors, targeting the active kinase conformation, but their effectiveness is limited by ongoing JAK-STAT signaling. To overcome these limitations, next-generation therapies, such as type II JAK2 inhibitors and pseudokinase domain inhibitors, are being developed to target inactive kinase conformations and alternative signaling pathways. Furthermore, combination therapies with PI3K, mTOR, CDK4/6 inhibitors, and epigenetic modulators are being investigated for their potential synergistic effects, aiming for deeper and more durable responses in MPN patients.

Expert opinion: Next-generation JAK2 inhibitors are needed to enhance current MPNs treatments by overcoming resistance, improving selectivity, targeting specific patient groups, and exploring combination therapies. Addressing challenges in drug design, preclinical testing, and clinical trials is crucial. Developing dual or multiple inhibitors targeting JAK2 and other MPN-related pathways is urgent to address complex signaling networks and improve efficacy.

Introduction: Cancer remains a leading cause of death worldwide with traditional treatments like chemotherapy, and radiotherapy becoming less effective due to multidrug resistance (MDR). This highlights the necessity for novel chemotherapeutics like chalcone-based compounds, which demonstrate broad anti-cancer properties and target multiple pathways. These compounds hold promise for improving cancer treatment outcomes compared to existing therapies.

Areas covered: This review provides a comprehensive synopsis of the recent literature (2018-2024) for anti-proliferative/anti-cancer activity of chalcones. It includes the identification of potential targets, their mechanisms of action, and possible modes of binding. Additionally, chalcone derivatives in preclinical trials are also discussed.

Expert opinion: Chalcones mark a significant stride in anticancer therapies due to their multifaceted approach in targeting various cellular pathways. Their ability to simultaneously target multiple pathways enables them to overcome drug resistance as compared to traditional therapies. With well-defined mechanisms of action, these compounds can serve as lead molecules for designing new, more promising treatments. Continued progress in synthesis and structural optimization, along with promising results from preclinical trials, offers hope for the development of more potent molecules, heralding a new era in cancer therapeutics.

Introduction: Targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy through selective degradation of specific proteins by harnessing the cellular ubiquitin-proteasome system (UPS), which involves over 600 E3 ubiquitin ligases. Recent proteome profiling reported tumor-specific E3 ligases in human. Development of those tumor-specific E3 ligase ligands would provide a solution for tumor-specific TPD for effective cancer treatment.

Areas covered: This review provides a comprehensive list of E3 ligases found only in specific types of tumor from public databases and highlights examples of their ligands discovered through fragment-based approaches. It details their discovery process and potential applications for precise TPD and effective cancer treatments.

Expert opinion: Current TPD strategies using proteolysis-targeting chimeras (PROTACs) primarily utilize general E3 ligases, such as CRBN and VHL. Since these E3 ligases demonstrate effective protein degradation activity in most human cell types, CRBN and VHL-based PROTACs can exhibit undesired TPD in off-target tissues, which often leads to the side effects. Therefore, developing tumor-specific E3 ligase ligands can be crucial for effective cancer treatments. Fragment-based ligand discovery (FBLD) approaches would accelerate the identification of these tumor-specific E3 ligase ligands and associated PROTACs, thereby advancing the field of targeted cancer therapies.