Expert Opinion on Drug Discovery

INTRODUCTION: Analyses of orally administered FDA-approved drugs from 1990 to 1993 enabled the identification of a set of physiochemical properties known as Lipinski's Rule of Five (Ro5). The original Ro5 and extended versions still remain the reference criteria for drug development programs. Since many bioactive compounds do not conform to the Ro5, we validated the relevance of and adherence to these rulesets in a contemporary cohort of FDA-approved drugs. AREAS COVERED: The authors noted that a significant proportion of FDA-approved orally administered parent compounds from 2011 to 2022 deviate from the original Ro5 criteria (~38%) or the Ro5 with extensions (~53%)...

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INTRODUCTION: The concept of Digital Twins (DTs) translated to drug development and clinical trials describes virtual representations of systems of various complexities, ranging from individual cells to entire humans, and enables in silico simulations and experiments. DTs increase the efficiency of drug discovery and development by digitalizing processes associated with high economic, ethical, or social burden. The impact is multifaceted: DT models sharpen disease understanding, support biomarker discovery and accelerate drug development, thus advancing precision medicine...

INTRODUCTION: Introduced about 50 years ago, the model of Xenopus oocytes for the expression of recombinant proteins has gained a broad spectrum of applications. The authors herein review the benefits brought from using this model system, with a focus on modeling neurological disease mechanisms and application to drug discovery. AREAS COVERED: Using multiple examples spanning from ligand gated ion channels to transporters, this review presents, in the light of the latest publications, the benefits offered from using Xenopus oocytes...

INTRODUCTION: The PAQosome is a 12-subunit complex that acts as a co-factor of the molecular chaperones HSP90 and HSP70. This co-chaperone has been shown to participate in assembly and maturation of several protein complexes, including nuclear RNA polymerases, RNA processing factors, the ribosome, PIKKs, and others. Subunits of the PAQosome, adaptors, and clients have been reported to be involved in various diseases, making them interesting targets for drug discovery. AREA COVERED: In this review, the authors cover the detailed mechanisms of PAQosome and chaperone function...

INTRODUCTION: The pursuit of novel therapeutic agents for serious diseases such as cancer has been a global endeavor. Aptamers characteristic of high affinity, programmability, low immunogenicity, and rapid permeability hold great promise for the treatment of diseases. Yet obtaining the approval for therapeutic aptamers remains challenging. Consequently, researchers are increasingly devoted to exploring innovative strategies and technologies to advance the development of these therapeutic aptamers...

INTRODUCTION: The COVID-19 pandemic stimulated the development of several therapeutic tools with several degrees of success. Ensitrelvir, a protease inhibitor that blocks the replication of SARS-CoV-2, can reduce the viral load and the severity of symptoms in infected patients and become available for emergency use in Japan. Clinical trials showed a good tolerability profile although the potential for interactions with substrates, inhibitors, and inducers of CYP3A must be considered. The occurrence of resistance is also a matter of investigation...

INTRODUCTION: Bioluminescence is a well-established optical detection technique widely used in several bioanalytical applications, including high-throughput and high-content screenings. Thanks to advances in synthetic biology techniques and deep learning, a wide portfolio of luciferases is now available with tuned emission wavelengths, kinetics, and high stability. These luciferases can be implemented in the drug discovery and development pipeline, allowing high sensitivity and multiplexing capability...

BACKGROUND: The process of drug development and discovery is costly and slow. Although an understanding of molecular design principles and biochemical processes has progressed, it is essential to minimize synthesis-testing cycles. An effective approach is to analyze key heteroatoms, including oxygen and nitrogen. Herein, we present an analysis focusing on the utilization of nitrogen atoms in approved drugs. 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)...

INTRODUCTION: Acquired resistance caused by gatekeeper mutations has become a major challenge for approved kinase inhibitors used in the clinic. Consequently, the development of new-generation inhibitors or degraders to overcome clinical resistance has become an important research focus for the field. AREAS COVERED: This review summarizes the common gatekeeper mutations in druggable kinases and the constantly evolving inhibitors or degraders designed to overcome single or double mutations of gatekeeper residues...

INTRODUCTION: Nowadays, it is widely accepted that water molecules play a key role in binding a ligand to a molecular target. Neglecting water molecules in the process of molecular recognition was the result of several failures in the structure-based drug discovery campaign. The application of WaterMap, in particular WaterMap-guided molecular docking, enables the reasonably accurate and quick description of the location and energetics of water molecules at the ligand-protein interface...

INTRODUCTION: Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by beta-amyloid accumulation and tau protein hyperphosphorylation. The disease involves interconnected mechanisms, which can be clustered into two target-packs based on the affected proteins. Pack-1 focuses on beta-amyloid accumulation, oxidative stress, and metal homeostasis dysfunction, and Pack-2 involves tau protein, calcium homeostasis, and neuroinflammation. Against this background heterocyclic system, there is a powerful source of pharmacophores to develop effective small drugs to treat multifactorial diseases like Alzheimer's...

INTRODUCTION: Alzheimer's disease (AD) is a progressive, irreversible, and multifactorial brain disorder that gradually and insidiously destroys individual's memory, thinking, and other cognitive abilities. AREAS COVERED: In this perspective, the authors examine the complex and multifactorial nature of Alzheimer's disease and believe that the best approach to develop new drugs is the MTDL strategy, which obviously faces several challenges. These challenges include identifying the key combination of targets and their suitability for coordinated actions, as well as developing an acceptable pharmacokinetic and toxicological profile to deliver a drug candidate...

INTRODUCTION: Network representation can give a holistic view of relationships for biomedical entities through network topology. Link prediction estimates the probability of link formation between the pair of unconnected nodes. In the drug discovery process, the link prediction method not only enables the detection of connectivity patterns but also predicts the effects of one biomedical entity to multiple entities simultaneously and vice versa, which is useful for many applications. AREAS COVERED: The authors provide a comprehensive overview of network link prediction in drug discovery...

INTRODUCTION: Drug-binding kinetics has been increasingly recognized as an important factor to be considered in drug discovery. Long residence time could prolong the action of some drugs while produce toxicity on others. Early evaluation of the binding kinetics of drug candidates could reduce attrition rate late in the drug discovery process. Computational prediction of drug-binding kinetics is useful as compounds can be evaluated even before they are made. However, simulation of drug-binding kinetics is a challenging problem because of the long-time scale involved...

INTRODUCTION: Drug-induced liver injury (DILI) is a potentially lethal condition that heavily impacts the pharmaceutical industry, causing approximately 21% of drug withdrawals and 13% of clinical trial failures. Recent evidence suggests that the use of Liver-Chip technology in preclinical safety testing may significantly reduce DILI-related clinical trial failures and withdrawals. However, drug developers and regulators would benefit from guidance on the integration of Liver-Chip data into decision-making processes to facilitate the technology's adoption...

INTRODUCTION: Translation is about successfully bringing findings from preclinical contexts into the clinic. This transfer is challenging as clinical trials frequently fail despite positive preclinical results. Limited robustness of preclinical research has been marked as one of the drivers of such failures. One suggested solution is to improve the external validity of in vitro and in vivo experiments via a suite of complementary strategies. AREAS COVERED: In this review, the authors summarize the literature available on different strategies to improve external validity in in vivo , in vitro , or ex vivo experiments; systematic heterogenization; generalizability tests; and multi-batch and multicenter experiments...

INTRODUCTION: Computer-aided drug design (CADD) is a computational approach used to discover, develop, and analyze drugs and active molecules with similar biochemical properties. Molecular simulation technology has significantly accelerated drug research and reduced manufacturing costs. It is an optimized drug discovery method that greatly improves the efficiency of novel drug development processes. AREASCOVERED: This review discusses the development of molecular simulations of effective cancer inhibitors and traces the main outcomes of in silico studies by introducing representative categories of six important anticancer targets...

INTRODUCTION: Graphene-based materials (GBMs) have unique physicochemical properties that make them extremely attractive as platforms for the design of new drugs. Indeed, their bidimensional (2D) morphology, high surface area, mechanical and optical properties, associated to different possibilities for functionalization of their surface, provides opportunities for their use as nanomedicines for drug delivery and/or phototherapies. AREAS COVERED: This opinion paper provides an overview of the current status of GBMs in drug design, with a focus on their therapeutic applications, potential environmental and health risks, and some controversial results...

INTRODUCTION: The Ca2+ signaling toolkit is currently under investigation as a potential target for addressing the threat of cancer. A growing body of evidence suggests that calcium signaling plays a crucial role in promoting various aspects of cancer, including cell proliferation, progression, drug resistance, and migration-related activities. Consequently, focusing on these altered Ca2+ transporting proteins has emerged as a promising area of research for cancer treatment. AREAS COVERED: This review highlights the existing research on the role of Ca2+ -transporting proteins in cancer progression...