Central Nervous System Drug Delivery Research Articles

Nanomedicine: A New Frontier in Alzheimer's Disease Drug Targeting.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting elderly individuals, characterized by progressive cognitive decline leading to dementia. This review examines the challenges posed by anatomical and biochemical barriers such as the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), and p-glycoproteins in delivering effective therapeutic agents to the central nervous system (CNS) for AD treatment. This article outlines the fundamental role of acetylcholinesterase inhibitors (AChEIs) and NMDA(N-Methyl-D-Aspartate) receptor antagonists in conventional AD therapy and highlights their limitations in terms of brain-specific delivery. It delves into the intricacies of BBB and pglycoprotein-mediated efflux mechanisms that impede drug transport to the CNS. The review further discusses cutting-edge nanomedicine-based strategies, detailing their composition and mechanisms that enable effective bypassing of BBB and enhancing drug accumulation in brain tissues. Conventional therapies, namely AChEIs and NMDA receptor antagonists, have shown limited efficacy and are hindered by suboptimal brain penetration. The advent of nanotechnology-driven therapeutic delivery systems offers promising strategies to enhance CNS targeting and bioavailability, thereby addressing the shortcomings of conventional treatments. Various nanomedicines, encompassing polymeric and metallic nanoparticles (MNPs), solid lipid nanoparticles (SLNs), liposomes, micelles, dendrimers, nanoemulsions, and carbon nanotubes, have been investigated for their potential in delivering anti-AD agents like AChEIs, polyphenols, curcumin, and resveratrol. These nanocarriers exhibit the ability to traverse the BBB and deliver therapeutic payloads to the brain, thereby holding immense potential for effective AD treatment and early diagnostic approaches. Notably, nanocarriers loaded with AChEIs have shown promising results in preclinical studies, exhibiting improved therapeutic efficacy and sustained release profiles. This review underscores the urgency of innovative drug delivery approaches to overcome barriers in AD therapy. Nanomedicine-based solutions offer a promising avenue for achieving effective CNS targeting, enabling enhanced bioavailability and sustained therapeutic effects. As ongoing research continues to elucidate the complexities of CNS drug delivery, these advancements hold great potential for revolutionizing AD treatment and diagnosis.

Hydrogel nanoparticles as new drug delivery system for CNS disorders

AbstractPrevious studies have shown that more than one million individuals suffer from central nervous system (CNS) diseases worldwide. Nanogels are a good way to deliver drugs because they are ultra‐stable, can hold a lot of drugs, have a core‐shell structure, are very permeable, and can get into brain tissue both in the lab and in living organisms. The blood‐brain barrier (BBB) and the blood‐cerebrospinal fluid barrier (BCSFB) make it harder to deliver therapies to specific areas of the CNS because drugs can′t get into the brain well enough. However, these barriers help treat neurological disorders like epilepsy, neurodegenerative diseases, brain tumors, and ischemic stroke. A number of biological studies suggest that nano‐additives may improve the shape, mechanical properties, electrical conductivity, and biological activities of hydrogels. The creation of nanogels for CNS drug delivery, their early preclinical success, and their potential for neurotoxicity are all examined in this research. This study looks at techniques that are almost ready for clinical use, a preclinical delivery system for the CNS, and the use of nanogels as a successful BBB‐penetration method. It also examines the main difficulties that nanogels must overcome in order to provide the most effective therapeutic care for CNS illnesses.

CNS Drug Delivery in Stroke: Improving Therapeutic Translation From the Bench to the Bedside.

Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials.

Exosomes encapsulated in hydrogels for effective central nervous system drug delivery.

The targeted delivery of pharmacologically active molecules, metabolites, and growth factors to the brain parenchyma has become one of the major challenges following the onset of neurodegeneration and pathological conditions. The therapeutic effect of active biomolecules is significantly impaired after systemic administration in the central nervous system (CNS) because of the blood-brain barrier (BBB). Therefore, the development of novel therapeutic approaches capable of overcoming these limitations is under discussion. Exosomes (Exo) are nano-sized vesicles of endosomal origin that have a high distribution rate in biofluids. Recent advances have introduced Exo as naturally suitable bio-shuttles for the delivery of neurotrophic factors to the brain parenchyma. In recent years, many researchers have attempted to regulate the delivery of Exo to target sites while reducing their removal from circulation. The encapsulation of Exo in natural and synthetic hydrogels offers a valuable strategy to address the limitations of Exo, maintaining their integrity and controlling their release at a desired site. Herein, we highlight the current and novel approaches related to the application of hydrogels for the encapsulation of Exo in the field of CNS tissue engineering.

Nanocarrier-mediated curcumin delivery: An adjuvant strategy for CNS disease treatment.

Neurological disorders are a major global challenge, which counts for a substantial slice of disease burden around the globe. In these, the challenging landscape of central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and neuro-AIDS, demands innovative and novel therapeutic approaches. Curcumin, a versatile natural compound with antioxidant and anti-inflammatory properties, shows great potential as a CNS adjuvant therapy. However, its limited bioavailability and suboptimal permeability to the blood-brain barrier (BBB) hamper the therapeutic efficacy of curcumin. This review explores how nanocarrier facilitates curcumin delivery, which has shown therapeutic efficacy for various non-CNS diseases, for example, cancers, and can also revolutionize the treatment outcomes in patients with CNS diseases. Toward this, intranasal administration of curcumin as a non-invasive CNS drug delivery route can also aid its therapeutic outcomes as an adjuvant therapy for CNS diseases. Intranasal delivery of nanocarriers with curcumin improves the bioavailability of curcumin and its BBB permeability, which is instrumental in promoting its therapeutic potential. Furthermore, curcumin's inhibitory effect on efflux transporters will help to enhance the BBB and cellular permeability of various CNS drugs. The therapeutic potential of curcumin as an adjuvant has the potential to yield synergistic effects with CNS drugs and will help to reduce CNS drug doses and improve their safety profile. Taken together, this approach holds a promise for reshaping CNS disease management by maximizing curcumin's and other drugs' therapeutic benefits.

Drug Delivery to the Brain: Recent Advances and Unmet Challenges.

Brain cancers and neurodegenerative diseases are on the rise, treatments for central nervous system (CNS) diseases remain limited. Despite the significant advancement in drug development technology with emerging biopharmaceuticals like gene therapy or recombinant protein, the clinical translational rate of such biopharmaceuticals to treat CNS disease is extremely poor. The blood-brain barrier (BBB), which separates the brain from blood and protects the CNS microenvironment to maintain essential neuronal functions, poses the greatest challenge for CNS drug delivery. Many strategies have been developed over the years which include local disruption of BBB via physical and chemical methods, and drug transport across BBB via transcytosis by targeting some endogenous proteins expressed on brain-capillary. Drug delivery to brain is an ever-evolving topic, although there were multiple review articles in literature, an update is warranted due to continued growth and new innovations of research on this topic. Thus, this review is an attempt to highlight the recent strategies employed to overcome challenges of CNS drug delivery while emphasizing the necessity of investing more efforts in CNS drug delivery technologies parallel to drug development.

Cu(ATSM) Increases P-Glycoprotein Expression and Function at the Blood-Brain Barrier in C57BL6/J Mice.

P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), is critical in preventing brain access to substrate drugs and effluxing amyloid beta (Aβ), a contributor to Alzheimer's disease (AD). Strategies to regulate P-gp expression therefore may impact central nervous system (CNS) drug delivery and brain Aβ levels. As we have demonstrated that the copper complex copper diacetyl bis(4-methyl-3-thiosemicarbazone) (Cu(ATSM)) increases P-gp expression and function in human brain endothelial cells, the present study assessed the impact of Cu(ATSM) on expression and function of P-gp in mouse brain endothelial cells (mBECs) and capillaries in vivo, as well as in peripheral organs. Isolated mBECs treated with Cu(ATSM) (100 nM for 24 h) exhibited a 1.6-fold increase in P-gp expression and a 20% reduction in accumulation of the P-gp substrate rhodamine 123. Oral administration of Cu(ATSM) (30 mg/kg/day) for 28 days led to a 1.5 & 1.3-fold increase in brain microvascular and hepatic expression of P-gp, respectively, and a 20% reduction in BBB transport of [3H]-digoxin. A metallomic analysis showed a 3.5 and 19.9-fold increase in Cu levels in brain microvessels and livers of Cu(ATSM)-treated mice. Our findings demonstrate that Cu(ATSM) increases P-gp expression and function at the BBB in vivo, with implications for CNS drug delivery and clearance of Aβ in AD.

A systematic review on application of nano-carriers loaded with drug in the treatment of neurological disorders

The central nervous system disorders represent a worldwide public health problem. Neuro-degeneration is associated with many transitions in brain including synaptic disorder and neuro-cognition decline. It is shielded by a barrier which controls the entry of compounds into the brain known as blood brain barrier (BBB), there by regulating brain homeostasis. In achieving a therapeutic amount of drug to the proper site of action in the body and then maintaining the desired amount of drug concentration for a sufficient time interval to be clinically effective for treatment. Particularly, neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) are becoming further established in the elderly inhabitants of the society. These ailments usually encompass advanced degeneration & neuronal loss, rendering these disorders spread and difficult to treat. There are various types of pharmaceutical approaches to treat the neurological disorders. The drug loaded Nano-carriers are one of them. In this review, we will address the different applications of drug loaded Nano-carriers in the treatment of various neurological disorders. The Nano-carriers developed to enhance drug delivery across the BBB include micelles, exosomes, liposomes, nanotubes, nanoparticle, Nano emulsions, dendrimers, Nano gels, and quantum dots, etc. The recent developments in Nano-carriers’ implementation through size/charge optimization and surface modifications like PE Gylation, targeting delivery, and coating with surfactants have been discussed, and a detailed description of the Nano-scaled pharmaceutical delivery devices employed for the treatment of central nervous system disorders has also been defined. This review provides a brief overview of the variety of carriers employed for central nervous system drug and diagnostic probes delivery.

The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases.

As major public health concerns associated with a rapidly growing aging population, neurodegenerative diseases (NDDs) and neurological diseases are important causes of disability and mortality. Neurological diseases affect millions of people worldwide. Recent studies have indicated that apoptosis, inflammation, and oxidative stress are the main players of NDDs and have critical roles in neurodegenerative processes. During the aforementioned inflammatory/apoptotic/oxidative stress procedures, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway plays a crucial role. Considering the functional and structural aspects of the blood-brain barrier, drug delivery to the central nervous system is relatively challenging. Exosomes are nanoscale membrane-bound carriers that can be secreted by cells and carry several cargoes, including proteins, nucleic acids, lipids, and metabolites. Exosomes significantly take part in the intercellular communications due to their specific features including low immunogenicity, flexibility, and great tissue/cell penetration capabilities. Due to their ability to cross the blood-brain barrier, these nano-sized structures have been introduced as proper vehicles for central nervous system drug delivery by multiple studies. In the present systematic review, we highlight the potential therapeutic effects of exosomes in the context of NDDs and neurological diseases by targeting the PI3K/Akt/mTOR signaling pathway.

Antarctic Krill Oil Exhibited Synergistic Effects with Nobiletin and Theanine on Regulating Ligand-Specific Receptor-Mediated Transcytosis in Blood-Brain Barrier by Inhibiting Alkaline Phosphatase in SAMP8 Mice.

Blood-brain barrier (BBB) impairment is related to the development of Alzheimer's disease (AD), which is dependent not only on tight junction but also on transcytosis of brain endothelial cells (BECs) in the BBB. Aging induces the decrease of ligand-specific receptor-mediated transcytosis (RMT) and the increase of non-specific caveolar transcytosis in BECs, which lead to the entry into parenchyma of neurotoxic proteins and the smaller therapeutic index in central nervous system drug delivery, further provoking neurodegenerative disease. A previous study suggests that sea-derived Antarctic krill oil (AKO) exhibits synergistic effects with land-derived nobiletin (NOB) and theanine (THE) on ameliorating memory and cognitive deficiency in SAMP8 mice. However, it is still unclear whether BBB change is involved. Hence, the effects of AKO combined with NOB and THE on aging-induced BBB impairment, including tight junction between BECs, ligand-specific RMT, and non-specific caveolar transcytosis in BECs, are investigated. The results suggest that AKO exhibits synergistic effects with NOB and THE on regulating ligand-specific RMT in BBB by inhibiting alkaline phosphatase (ALPL). The study provides a potential strategy candidate or targeted dietary patterns to prevent and treat AD by improving the BBB function.

Intranasal Polymeric and Lipid-Based Nanocarriers for CNS Drug Delivery

Nanomedicine is currently focused on the design and development of nanocarriers that enhance drug delivery to the brain to address unmet clinical needs for treating neuropsychiatric disorders and neurological diseases. Polymer and lipid-based drug carriers are advantageous for delivery to the central nervous system (CNS) due to their safety profiles, drug-loading capacity, and controlled-release properties. Polymer and lipid-based nanoparticles (NPs) are reported to penetrate the blood-brain barrier (BBB) and have been extensively assessed in in vitro and animal models of glioblastoma, epilepsy, and neurodegenerative disease. Since approval by the Food and Drug Administration (FDA) of intranasal esketamine for treatment of major depressive disorder, intranasal administration has emerged as an attractive route to bypass the BBB for drug delivery to the CNS. NPs can be specifically designed for intranasal administration by tailoring their size and coating with mucoadhesive agents or other moieties that promote transport across the nasal mucosa. In this review, unique characteristics of polymeric and lipid-based nanocarriers desirable for drug delivery to the brain are explored in addition to their potential for drug repurposing for the treatment of CNS disorders. Progress in intranasal drug delivery using polymeric and lipid-based nanostructures for the development of treatments of various neurological diseases are also described.

Drug Permeability: From the Blood-Brain Barrier to the Peripheral Nerve Barriers.

Drug delivery into the peripheral nerves and nerve roots has important implications for effective local anesthesia and treatment of peripheral neuropathies and chronic neuropathic pain. Similar to drugs that need to cross the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) to gain access to the central nervous system (CNS), drugs must cross the peripheral nerve barriers (PNB), formed by the perineurium and blood-nerve barrier (BNB) to modulate peripheral axons. Despite significant progress made to develop effective strategies to enhance BBB permeability in therapeutic drug design, efforts to enhance drug permeability and retention in peripheral nerves and nerve roots are relatively understudied. Guided by knowledge describing structural, molecular and functional similarities between restrictive neural barriers in the CNS and peripheral nervous system (PNS), we hypothesize that certain CNS drug delivery strategies are adaptable for peripheral nerve drug delivery. In this review, we describe the molecular, structural and functional similarities and differences between the BBB and PNB, summarize and compare existing CNS and peripheral nerve drug delivery strategies, and discuss the potential application of selected CNS delivery strategies to improve efficacious drug entry for peripheral nerve disorders.

Development of a Nanoparticle-Based Approach for the Blood–Brain Barrier Passage in a Murine Model of Amyotrophic Lateral Sclerosis

The development of nanoparticles (NPs) to enable the passage of drugs across blood-brain barrier (BBB) represents one of the main challenges in neuropharmacology. In recent years, NPs that are able to transport drugs and interact with brain endothelial cells have been tested. Here, we investigated whether the functionalization of avidin-nucleic-acid-nanoassembly (ANANAS) with apolipoprotein E (ApoE) would allow BBB passage in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Our results demonstrated that ANANAS was able to transiently cross BBB to reach the central nervous system (CNS), and ApoE did not enhance this property. Next, we investigated if ANANAS could improve CNS drug delivery. To this aim, the steroid dexamethasone was covalently linked to ANANAS through an acid-reversible hydrazone bond. Our data showed that the steroid levels in CNS tissues of SOD1G93A mice treated with nanoformulation were below the detection limit. This result demonstrates that the passage of BBB is not sufficient to guarantee the release of the cargo in CNS and that a different strategy for drug tethering should be devised. The present study furthermore highlights that NPs can be useful in improving the passage through biological barriers but may limit the interaction of the therapeutic compound with the specific target.

Exosomes as CNS Drug Delivery Tools and Their Applications

Central nervous system (CNS) diseases threaten the health of people all over the world. However, due to the structural and functional particularities of the brain and spinal cord, CNS-targeted drug development is rather challenging. Exosomes are small cellular vesicles with lipid bilayers that can be secreted by almost all cells and play important roles in intercellular communication. The advantages of low immunogenicity, the ability to cross the blood-brain barrier, and the flexibility of drug encapsulation make them stand out among CNS drug delivery tools. Herein, we reviewed the research on exosomes in CNS drug delivery over the past decade and outlined the impact of the drug loading mode, administration route, and engineered modification on CNS targeting. Finally, we highlighted the problems and prospects of exosomes as CNS drug delivery tools.

Role of 3D Printing in the Development of Biodegradable Implants for Central Nervous System Drug Delivery.

Increased life expectancy has led to a rise in age-related disorders including neurological diseases such as Alzheimer's disease and Parkinson's disease. Limited progress has been made in the development of clinically translatable therapies for these central nervous system (CNS) diseases. Challenges including the blood-brain barrier, brain complexity, and comorbidities in the elderly population are some of the contributing factors toward lower success rates. Various invasive and noninvasive ways are being employed to deliver small and large molecules across the brain. Biodegradable, implantable drug-delivery systems have gained lot of interest due to advantages such as sustained and targeted delivery, lower side effects, and higher patient compliance. 3D printing is a novel additive manufacturing technique where various materials and printing techniques can be used to fabricate implants with the desired complexity in terms of mechanical properties, shapes, or release profiles. This review discusses an overview of various types of 3D-printing techniques and illustrative examples of the existing literature on 3D-printed systems for CNS drug delivery. Currently, there are various technical and regulatory impediments that need to be addressed for successful translation from the bench to the clinical stage. Overall, 3D printing is a transformative technology with great potential in advancing customizable drug treatment in a high-throughput manner.

A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders.

Gels are attractive candidates for drug delivery because they are easily producible while offering sustained and/or controlled drug release through various mechanisms by releasing the therapeutic agent at the site of action or absorption. Gels can be classified based on various characteristics including the nature of solvents used during preparation and the method of cross-linking. The development of novel gel systems for local or systemic drug delivery in a sustained, controlled, and targetable manner has been at the epitome of recent advances in drug delivery systems. Cross-linked gels can be modified by altering their polymer composition and content for pharmaceutical and biomedical applications. These modifications have resulted in the development of stimuli-responsive and functionalized dosage forms that offer many advantages for effective dosing of drugs for Central Nervous System (CNS) conditions. In this review, the literature concerning recent advances in cross-linked gels for drug delivery to the CNS are explored. Injectable and non-injectable formulations intended for the treatment of diseases of the CNS together with the impact of recent advances in cross-linked gels on studies involving CNS drug delivery are discussed.

Solid Lipid Nanoparticles: A Nano Drug Carrying System in Treatment of Nervous Diseases

Solid lipid nanoparticle (SLN) is a unique colloidal system used to deliver drugs which is nontoxic, biodegradable, showing good biocompatibility, and have small particle size. The possibility of SLN to deliver the brain drugs without damaging the brain-blood barrier (BBB) makes SLN an advanced central nervous system (CNS) drug delivery system. SLNs delivering drugs to CNS are mostly prepared by applying high energy homogenization method to achieve a better surface modification. The central topic of this article is how the SLN can overcome the BBB and help treat the central neural system disease. Also, SLNs contain levodopa can go through the BBB to help treat Parkinson’s and SLNs coated with chitosan and loaded with ferric acid to treat Alzheimer’s Disease (AD) are highlighted in this article. The effectiveness of SLNs compared with traditional therapy is shown in the article. Additionally, further studies are needed to focus on higher encapsulation efficiency and drug load efficiency as well as the targeted intranasal drug delivery.

Chitosan-modified hollow manganese dioxide nanoparticles loaded with resveratrol for the treatment of spinal cord injury

Spinal cord injury (SCI) is a serious central nervous system disease, and secondary injury, including oxidative stress, the inflammatory response and accompanying neuronal apoptosis, will aggravate the condition. Due to the existence of the blood–spinal cord barrier (BSCB), the existing drugs for SCI treatment are difficulty to reach the injury site and thus their efficacy is limited. In this study, we designed chitosan-modified hollow manganese dioxide nanoparticles (CM) for the delivery of resveratrol to help it pass through the BSCB. Resveratrol (Res), a poorly soluble drug, was adsorbed into CM with a particle size of approximately 130 nm via the adsorption method, and the drug loading reached 21.39 ± 2.53%. In vitro dissolution experiment, the Res release of the loaded sample (CMR) showed slowly release behavior and reached about 87% at 36 h. In vitro at the cellular level and in vivo at the animal level experiments demonstrated that CMR could alleviate significantly oxidative stress by reducing level of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and increasing glutathione peroxidase (GSH) level. Additionally, immunofluorescence (iNOS, IL-1β, and Cl caspase-3) and western blot (iNOS, cox-2, IL-1β, IL-10, Cl caspase-3, bax, and bcl-2) were used to detect the expression of related factors, which verified that CMR could also reduce inflammation and neuronal apoptosis. These results indicated that CM, as a potential central nervous system drug delivery material, was suitable for SCI treatment.

Brain Cancer Chemotherapy through a Delivery System across the Blood-Brain Barrier into the Brain Based on Receptor-Mediated Transcytosis Using Monoclonal Antibody Conjugates.

Advances in pharmacotherapy have brought extraordinary benefits to humanity. However, unmet medical needs in patients remain, particularly in the treatment of central nervous system (CNS) diseases and cancers. CNS drug delivery into the brain across the endothelium is difficult due to the blood-brain barrier (BBB), which is composed mainly of tight junctions and efflux transporters, such as multiple drug resistance 1 (MDR1) (P-glycoprotein). On the other hand, the development of anti-cancer drugs is a challenging task due to their frequent off-target side effects and the complicated mechanisms of cancer pathogenesis and progression. Brain cancer treatment options are surgery, radiation therapy, and chemotherapy. It is difficult to remove all tumor cells, even by surgical removal after a craniotomy. Accordingly, innovative brain cancer drugs are needed. Currently, antibody (Ab) drugs that show high therapeutic effects are often used clinically. Furthermore, antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan, an anti-HER2 (human epidermal receptor 2) ADC with low-molecular cancer drugs through the suitable linker, have been developed. In the case of trastuzumab deruxtecan, it is internalized into cancer cells across the membrane via receptor-mediated endocytosis. Moreover, it is reported that drug delivery into the brain across the BBB was carried out via receptor-mediated transcytosis (RMT), using anti-receptor Abs as a vector against the transferrin receptor (TfR) or insulin receptor (InsR). Thus, anti-TfR ADCs with cancer drugs are promising brain cancer agents due to their precise distribution and low side effects. In this review, I introduce the implementations and potential of brain cancer drug delivery into the brain across the BBB, based on RMT using ADCs.

An In Silico Explainable Multiparameter Optimization Approach for De Novo Drug Design against Proteins from the Central Nervous System.

The aim of drug design and development is to produce a drug that can inhibit the target protein and possess a balanced physicochemical and toxicity profile. Traditionally, this is a multistep process where different parameters such as activity and physicochemical and pharmacokinetic properties are optimized sequentially, which often leads to high attrition rate during later stages of drug design and development. We have developed a deep learning-based de novo drug design method that can design novel small molecules by optimizing target specificity as well as multiple parameters (including late-stage parameters) in a single step. All possible combinations of parameters were optimized to understand the effect of each parameter over the other parameters. An explainable predictive model was used to identify the molecular fragments responsible for the property being optimized. The proposed method was applied against the human 5-hydroxy tryptamine receptor 1B (5-HT1B), a protein from the central nervous system (CNS). Various physicochemical properties specific to CNS drugs were considered along with the target specificity and blood-brain barrier permeability (BBBP), which act as an additional challenge for CNS drug delivery. The contribution of each parameter toward molecule design was identified by analyzing the properties of generated small molecules from optimization of all possible parameter combinations. The final optimized generative model was able to design similar inhibitors compared to known inhibitors of 5-HT1B. In addition, the functional groups of the generated small molecules that guide the BBBP predictive model were identified through feature attribution techniques.