Front Pharmacol. 2022 Oct 26;13:1028356. doi: 10.3389/fphar.2022.1028356. eCollection 2022.

ABSTRACT

Given the high whittling down rates, high costs, and moderate pace of new medication, revelation, and improvement, repurposing "old" drugs to treat typical and uncommon illnesses is progressively becoming an appealing proposition. Drug repurposing is the way toward utilizing existing medications in treating diseases other than the purposes they were initially designed for. Faced with scientific and economic challenges, the prospect of discovering new medication indications is enticing to the pharmaceutical sector. Medication repurposing can be used at various stages of drug development, although it has shown to be most promising when the drug has previously been tested for safety. We describe strategies of drug repurposing for Parkinson's disease, which is a neurodegenerative condition that primarily affects dopaminergic neurons in the substantia nigra. We also discuss the obstacles faced by the repurposing community and suggest new approaches to solve these challenges so that medicine repurposing can reach its full potential.

PMID:36386233 | PMC:PMC9643740 | DOI:10.3389/fphar.2022.1028356

Pharmacopsychiatry. 2022 Nov 16. doi: 10.1055/a-1970-3453. Online ahead of print.

ABSTRACT

Drug repurposing is a strategy to identify new indications for already approved drugs. A recent successful example in psychiatry is ketamine, an anesthetic drug developed in the 1960s, now approved and clinically used as a fast-acting antidepressant. Here, we describe the potential of dexmedetomidine as a psychopharmacological repurposing candidate. This α2-adrenoceptor agonist is approved in the US and Europe for procedural sedation in intensive care. It has shown fast-acting inhibitory effects on perioperative stress-related pathologies, including psychomotor agitation, hyperalgesia, and neuroinflammatory overdrive, proving potentially useful in clinical psychiatry. We offer an overview of the pharmacological profile and effects of dexmedetomidine with potential utility for the treatment of neuropsychiatric symptoms. Dexmedetomidine exerts fast-acting and robust sedation, anxiolytic, analgesic, sleep-modulating, and anti-inflammatory effects. Moreover, the drug prevents postoperative agitation and delirium, possibly via neuroprotective mechanisms. While evidence in animals and humans supports these properties, larger controlled trials in clinical samples are generally scarce, and systematic studies with psychiatric patients do not exist. In conclusion, dexmedetomidine is a promising candidate for an experimental treatment targeting stress-related pathologies common in neuropsychiatric disorders such as depression, anxiety disorders, and posttraumatic stress disorder. First small proof-of-concept studies and then larger controlled clinical trials are warranted in psychiatric populations to test the feasibility and efficacy of dexmedetomidine in these conditions.

PMID:36384232 | DOI:10.1055/a-1970-3453

Int J Pharm. 2022 Nov 13:122400. doi: 10.1016/j.ijpharm.2022.122400. Online ahead of print.

ABSTRACT

The potential of intra-venous gallium nitrate (GaN) administration against Pseudomonas aeruginosa pneumonia was recently demonstrated in mice and in cystic fibrosis (CF) patients. Likewise, the added value of direct lung delivery of Ga(III) has been shown in rats. Therefore, the design of a drug delivery system specifically engineered for Ga(III) inhalation is imperative to improve its accumulation in lungs. To this purpose, Ga(III) was efficiently encapsulated into hyaluronic acid/chitosan nanoparticles (Ga_HA/CS NPs), whose features were tuned to facilitate access to the target by overcoming mucus and biofilm surrounding bacteria. Then, to improve in vivo lung deposition, Ga_HA/CS NPs were engineered into mannitol-based NEM (Ga_Man NEM). The powders showed optimal in vitro aerosol performance, and sustained release kinetics in lung lining fluids. Moreover, good tolerability and antimicrobial properties were shown in vitro. Intratracheal insufflation of Ga_Man NEM in rats resulted in a significant improvement of Ga(III) persistence in the lungs coupled to a lower Ga(III) concentration in plasma and urine, compared to GaN solution. Noteworthy, the developed formulation significantly modifies the unfavorable Ga(III) kinetic increasing the Ga(III) to the lung and preventing Ga(III) accumulation in the kidney, key responsible for adverse effects, conclusively demonstrating the benefit of Ga_Man NEM to exploit the therapeutic effect of Ga(III) via inhalation route.

PMID:36384182 | DOI:10.1016/j.ijpharm.2022.122400

Assay Drug Dev Technol. 2022 Nov 16. doi: 10.1089/adt.2022.097. Online ahead of print.

NO ABSTRACT

PMID:36383145 | DOI:10.1089/adt.2022.097

Clin Kidney J. 2022 May 19;15(12):2200-2213. doi: 10.1093/ckj/sfac143. eCollection 2022 Dec.

ABSTRACT

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycaemia and hypertension. In this scenario, drug repurposing constitutes an economic and feasible approach based on the discovery of useful activities for old drugs. Pentoxifylline is a nonselective phosphodiesterase inhibitor currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to anti-inflammatory and antifibrotic effects in diabetic patients treated with this old known drug, which makes pentoxifylline a candidate for repurposing in diabetic kidney disease.

PMID:36381364 | PMC:PMC9664582 | DOI:10.1093/ckj/sfac143

Iran J Biotechnol. 2022 Jul 1;20(3):e2968. doi: 10.30498/ijb.2022.269817.2968. eCollection 2022 Jul.

ABSTRACT

BACKGROUND: As the most prevalent form of liver cancer, hepatocellular carcinoma (HCC) ranks the fifth highest cause of cancer-related death worldwide. Despite recent advancements in diagnostic and therapeutic techniques, the prognosis for HCC is still unknown.

OBJECTIVES: This study aimed to identify potential genes contributing to HCC pathogenicity.

MATERIALS AND METHODS: To this end, we examined the GSE39791 microarray dataset, which included 72 HCC samples and 72 normal samples. An investigation of co-expression networks using WGCNA found a highly conserved blue module with 665 genes that were strongly linked to HCC.

RESULTS: APOF, NAT2, LCAT, TTC36, IGFALS, ASPDH, and VIPR1 were the blue module's top 7 hub genes. According to the results of hub gene enrichment, the most related issues in the biological process and KEGG were peroxisome organization and metabolic pathways, respectively. In addition, using the drug-target network, we discovered 19 FDA-approved medication candidates for different reasons that might potentially be employed to treat HCC patients through the modulation of 3 hub genes of the co-expression network (LCAT, NAT2, and VIPR1). Our findings also demonstrated that the 3 scientifically validated miRNAs regulated the co-expression network by the VIPR1 hub gene.

CONCLUSION: We found co-expressed gene modules and hub genes linked with HCC advancement, offering insights into the mechanisms underlying HCC progression as well as some potential HCC treatments.

PMID:36381283 | PMC:PMC9618018 | DOI:10.30498/ijb.2022.269817.2968

OMICS. 2022 Nov 15. doi: 10.1089/omi.2022.0138. Online ahead of print.

ABSTRACT

The mechanisms of systemic autoimmune diseases (ADs) are still not clearly understood. Understanding the etiology of systemic ADs and identifying new therapeutic targets require a systems science approach. Using publicly available transcriptome data and bioinformatic analysis, we investigated the differential gene expression profiles of patients with scleroderma, systemic lupus erythematosus, and Sjogren's syndrome. Of these common differentially expressed gene signatures, 208 were regulated in the same direction (either upregulated or downregulated in all datasets) and used for drug repositioning. Six small molecule drug candidates (KU-0063794, YM-155 [sepantronium bromide], MST-312 [telomerase inhibitor IX], PLX-4720, ZM 336372, and 528116.cdx [PIK-75]) were discovered by drug repositioning as potential therapeutics for systemic ADs. The Search Tool for Chemical Interactions was used to find the anticipated target genes of the repositioned molecules. The PI3K/AKT pathway topped the list of common enriched pathways with the most anticipated target genes of the six repositioned small molecules. We also report here the molecular docking findings on the binding affinity between the repositioned drug candidates and genes from the protein-protein interaction network modules of anticipated target genes. Taken together, this study provides new insights and opens up new possibilities on both pathogenesis and treatment of systemic ADs through drug repositioning.

PMID:36378860 | DOI:10.1089/omi.2022.0138

Kidney Int. 2022 Oct 29:S0085-2538(22)00911-5. doi: 10.1016/j.kint.2022.09.029. Online ahead of print.

ABSTRACT

Blood pressure is regulated by a complex neurohumoral system including the renin-angiotensin-aldosterone system, natriuretic peptides, endothelial pathways, the sympathetic nervous system, and the immune system. This review charts the evolution of our understanding of the genomic basis of hypertension at increasing resolution over the last 5 decades from monogenic causes to polygenic associations, spanning ∼30 monogenic rare variants and >1500 single nucleotide variants. Unexpected early wins from blood pressure genomics include deepening of our understanding of the complex causation of hypertension; refinement of causal estimates bidirectionally between blood pressure, risk factors, and outcomes through Mendelian randomization; risk stratification using polygenic risk scores; and opportunities for precision medicine and drug repurposing.

PMID:36377113 | DOI:10.1016/j.kint.2022.09.029

Mol Divers. 2022 Nov 14. doi: 10.1007/s11030-022-10561-y. Online ahead of print.

ABSTRACT

Breast cancer is recognized globally as one of the leading causes of malignant morbidity. It is a heterogeneous disease that accounts for 30 percent of all women diagnosed with cancer. To bring an anti-cancer drug from the bench to the bedside is an expensive and time-consuming process. The drug repurposing approach targets new enemies (new diseases) with old weapons (known drugs). The present study identified an FDA-approved drug targeting the γ-secretase complex involved in the Notch signaling pathway in breast cancer stem cells (BCSCs). A literature survey and in-silico study identified Venetoclax as a γ-secretase inhibitor (GSI) from 1615 FDA-approved drug compounds. In-silico docking potential of Venetoclax was better than the standard γ-secretase inhibitor RO4929097. Also, the molecular dynamics simulations of 200 ns confirmed the stability of the Venetoclax-γ-secretase complex. These findings suggest that the use of Venetoclax represents a potential γ-secretase inhibitor in breast cancer stem cells. Eventually, the in vitro and clinical evaluation will be needed to confirm the potential chemopreventive and treatment effects of Venetoclax against breast cancer and breast cancer stem cells. Venetoclax appeared as the most promising drug of the 1615 FDA-approved drugs. Our in-silico findings suggest that Venetoclax may act as a γ-secretase inhibitor against the Notch signaling pathway in breast cancer stem cells.

PMID:36376717 | DOI:10.1007/s11030-022-10561-y

Int J Pharm. 2022 Nov 9:122379. doi: 10.1016/j.ijpharm.2022.122379. Online ahead of print.

ABSTRACT

Anthracyclines such as doxorubicin (Dox) are the preferred chemotherapeutics for several cancers. However, Dox-induced cardiotoxicity limits its therapeutic potential. Liposomal encapsulation of Dox has been used for patients with risk to develop Dox induced cardiotoxicity but does not surpass the efficacy of the unencapsulated drug. Statins are widely used as cholesterol lowering drugs and have also demonstrated cardioprotective activity in cancer patients undergoing Dox therapy. We developed a liposome loaded with Dox and simvastatin (Sim) and investigated their effect on cardiomyocytes and zebrafish larvae. Furthermore, we investigated if the doses required for cardioprotection compromised the cytotoxicity of Dox in mammary and prostate cancer cells. Combination of Sim and Dox reduced ROS generation in cardiomyocytes, both given as free drugs, or co-encapsulated in liposomes. In contrast, Sim potentiated ROS-generation and cytotoxic activity of Dox towards cancer cells also when co-encapsulated in liposomes. In zebrafish larvae, Sim treatment reduced Dox-induced cardiac affection, and the liposomes did not induce any sign of Dox-induced cardiotoxicity. Our results show that liposomal co-encapsulation of Sim and Dox can be an efficient way of further reducing the risk of cardiotoxic events of liposomal Dox, while retaining, or even potentiating the anti-cancer effect of Dox.

PMID:36370997 | DOI:10.1016/j.ijpharm.2022.122379

Biomed Pharmacother. 2022 Nov 9;157:113904. doi: 10.1016/j.biopha.2022.113904. Online ahead of print.

ABSTRACT

Neurodegenerative diseases have been a weighty problem in elder people who might be stricken with motor or/and cognition defects with lower life quality urging for effective treatment. Drugs are costly from development to market, so that drug repurposing, exploration of existing drugs for novel therapeutic purposes, becomes a wise and popular strategy to raise new treatment options. Clemastine fumarate, different from anti-allergic effect as H1 histamine antagonist, was screened and identified as promising drug for remyelination and autophagy enhancement. Surprisingly, fumarate salt also has similar effect. Hence, whether clemastine fumarate would make a protective impact on neurodegenerative diseases and what contribution fumarate probably makes are intriguing to us. In this review, we summarize the potential mechanism surrounding clemastine fumarate in current literature, and try to distinguish independent or synergistic effect between clemastine and fumarate, aiming to find worthwhile research direction for neurodegeneration diseases.

PMID:36370521 | DOI:10.1016/j.biopha.2022.113904

Alzheimers Res Ther. 2022 Nov 11;14(1):169. doi: 10.1186/s13195-022-01103-7.

ABSTRACT

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson's disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia.

PMID:36369100 | DOI:10.1186/s13195-022-01103-7

Neuropharmacology. 2022 Nov 8:109327. doi: 10.1016/j.neuropharm.2022.109327. Online ahead of print.

ABSTRACT

BACKGROUND: The prevalences of Alzheimer's disease (AD) and type 2 diabetes (T2D) continuously increase with the aging of world population. Clinical and epidemiological studies indicate that T2D is an important risk factor for AD. However, the mechanisms underlying the linkage of the two disorders are still not fully elucidated. The aim of this study is to explore the molecular mechanisms of their comorbidity and potential drug targets for AD treatment.

METHODS: We first compiled comprehensive lists of genes associated with AD and T2D, respectively. Then, we investigated the signatures of the shared genes and screened for interactions between the hub genes. Subsequently, we used Autodock Vina to perform molecular docking to predict new drug candidates. Lastly, structure and dynamics of docking results were examined by molecular dynamics simulation to verify drug reliability.

RESULTS: We obtained 917 AD-associated genes, 631 T2D-associated genes and 175 shared genes between the two disorders for subsequent analyses. Functional analysis revealed that metabolic process, lipid and atherosclerosis, AMPK signaling pathway, insulin resistance, chemokines and cytokines were enriched in the shared genes. In addition, 50 central hub genes were identified, including IL6, TNF, INS, IL1B, AKT1, VEGFA, IL10, TP53, PTGS2, TLR4, and others. Finally, we predicted new drug candidates (verdoheme and stannsoporfin) that could be potentially used for AD treatment.

CONCLUSIONS: Our study confirmed that there are important shared genes and pathways between AD and T2D, which may provide clues to reveal the molecular mechanism underlying the pathophysiology of the two diseases and help us to discover novel drug candidates for the treatment of AD. The results may also provide clues into identification of new targets and strategies for prevention and therapy of T2D that predisposes to AD.

PMID:36368623 | DOI:10.1016/j.neuropharm.2022.109327

PLoS One. 2022 Nov 11;17(11):e0277355. doi: 10.1371/journal.pone.0277355. eCollection 2022.

ABSTRACT

BACKGROUND: Patient interest in the use of cannabis-based medicines (CBMs) has increased in Australia. While recent policy and legislative changes have enabled health practitioners to prescribe CBMs for their patients, many patients still struggle to access CBMs. This paper employed a thematic analysis to submissions made to a 2019 Australian government inquiry into current barriers of patient access to medical cannabis.

METHODS: We identified 121 submissions from patients or family members (n = 63), government bodies (n = 5), non-government organisations (i.e., professional health bodies, charities, consumer organisations or advocacy groups; n = 25), medical cannabis and pharmaceutical industry (n = 16), and individual health professionals, academics, or research centres (n = 12). Data were coded using NVivo 12 software and thematically analysed. The findings were presented narratively using a modified Levesque's patient-centred access to care framework which includes: i) appropriateness; ii) availability and geographic accessibility; iii) acceptability; and iv) affordability.

RESULTS: Submissions from government agencies and professional health bodies consistently supported maintaining the current regulatory frameworks and access pathways, whereas an overwhelming majority of patients, advocacy groups and the medical cannabis industry described the current regulatory and access models as 'not fit for purpose'. These differing views seem to arise from divergent persepctives on (i) what and how much evidence is needed for policy and practice, and (ii) how patients should be given access to medical cannabis products amidst empirical uncertainty. Notwithstanding these differences, there were commonalities among some stakeholders regarding the various supply, regulatory, legislative, financial, and dispensing challenges that hindered timely access to CBMs.

CONCLUSIONS: Progress in addressing the fundamental barriers that determine if and how a patient accesses and uses CBMs needs i) a 'system-level' reform that gives due consideration to the geographic disparity in access to prescribers and medical cannabis, and ii) reframing societal and health professional's views of CBMs by decoupling recreational vs medical cannabis.

PMID:36367871 | DOI:10.1371/journal.pone.0277355

Chem Biol Drug Des. 2022 Nov 11. doi: 10.1111/cbdd.14179. Online ahead of print.

ABSTRACT

The coronavirus pandemic known as COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), threatens public health worldwide. Approval of COVID-19 vaccines and antiviral drugs have greatly reduced the severe cases and mortality rate. However, the continues mutations of viruses are challenging the efficacies of vaccines and antiviral drugs. Drug repurposing campaign has identified two JAK1/2 inhibitors ruxolitinib and baricitinib as potential antiviral drugs. Ruxolitinib and baricitinib exerts dual antiviral effect by modulation of inflammatory response via JAK1/2 and inhibition of viral entry via AAK1 and GAK. Inspired by this, in an effort to diversify chemical space, three analogues ((R)-8, (S)-8 and 9) of ruxolitinib and baricitinb were made using scaffold hopping strategy. Compound 9 displayed potent and comparable potencies against AAK1, JAK1 and JAK2 compared to Baricitinib. Notably, compound 9 showed better selectivity for AAK1, JAK1 and JAK2 over GAK. Besides, compound 9 displayed good druglikeness according to Lipinski's and Veber's rule. We thereby identified a potential lead compound 9, which might be used for the further development of anti-coronaviral therapy.

PMID:36366971 | DOI:10.1111/cbdd.14179

Viruses. 2022 Oct 31;14(11):2417. doi: 10.3390/v14112417.

ABSTRACT

The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given circa 7817 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies than in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both SARS-CoV-2 Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus, has virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.

PMID:36366514 | DOI:10.3390/v14112417

Pathogens. 2022 Nov 3;11(11):1291. doi: 10.3390/pathogens11111291.

ABSTRACT

Tuberculosis (TB) is one of the leading causes of death worldwide, consistently threatening public health. Conventional tuberculosis treatment requires a long-term treatment regimen and is associated with side effects. The efficacy of antitubercular drugs has decreased with the emergence of drug-resistant TB; therefore, the development of new TB treatment strategies is urgently needed. In this context, we present host-directed therapy (HDT) as an alternative to current tuberculosis therapy. Unlike antitubercular drugs that directly target Mycobacterium tuberculosis (Mtb), the causative agent of TB, HDT is an approach for treating TB that appropriately modulates host immune responses. HDT primarily aims to enhance the antimicrobial activity of the host in order to control Mtb infection and attenuate excessive inflammation in order to minimize tissue damage. Recently, research based on the repositioning of drugs for use in HDT has been in progress. Based on the overall immune responses against Mtb infection and the immune-evasion mechanisms of Mtb, this review examines the repositioned drugs available for HDT and their mechanisms of action.

PMID:36365041 | DOI:10.3390/pathogens11111291

Molecules. 2022 Nov 4;27(21):7553. doi: 10.3390/molecules27217553.

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV), belonging to the betacoronavirus genus can cause severe respiratory illnesses, accompanied by pneumonia, multiorgan failure, and ultimately death. CoVs have the ability to transgress species barriers and spread swiftly into new host species, with human-to-human transmission causing epidemic diseases. Despite the severe public health threat of MERS-CoV, there are currently no vaccines or drugs available for its treatment. MERS-CoV papain-like protease (PLpro) is a key enzyme that plays an important role in its replication. In the present study, we evaluated the inhibitory activities of doxorubicin (DOX) against the recombinant MERS-CoV PLpro by employing protease inhibition assays. Hydrolysis of fluorogenic peptide from the Z-RLRGG-AMC-peptide bond in the presence of DOX showed an IC50 value of 1.67 μM at 30 min. Subsequently, we confirmed the interaction between DOX and MERS-CoV PLpro by thermal shift assay (TSA), and DOX increased ΔTm by ~20 °C, clearly indicating a coherent interaction between the MERS-CoV PL protease and DOX. The binding site of DOX on MERS-CoV PLpro was assessed using docking techniques and molecular dynamic (MD) simulations. DOX bound to the thumb region of the catalytic domain of the MERS-CoV PLpro. MD simulation results showed flexible BL2 loops, as well as other potential residues, such as R231, R233, and G276 of MERS-CoV PLpro. Development of drug repurposing is a remarkable opportunity to quickly examine the efficacy of different aspects of treating various diseases. Protease inhibitors have been found to be effective against MERS-CoV to date, and numerous candidates are currently undergoing clinical trials to prove this. Our effort follows a in similar direction.

PMID:36364379 | DOI:10.3390/molecules27217553

Molecules. 2022 Nov 3;27(21):7522. doi: 10.3390/molecules27217522.

ABSTRACT

The SARS-CoV-2 non-structural protein 13 (nsp13) helicase is an essential enzyme for viral replication and has been identified as an attractive target for the development of new antiviral drugs. In detail, the helicase catalyzes the unwinding of double-stranded DNA or RNA in a 5' to 3' direction and acts in concert with the replication-transcription complex (nsp7/nsp8/nsp12). In this work, bioinformatics and computational tools allowed us to perform a detailed conservation analysis of the SARS-CoV-2 helicase genome and to further predict the druggable enzyme's binding pockets. Thus, a structure-based virtual screening was used to identify valuable compounds that are capable of recognizing multiple nsp13 pockets. Starting from a database of around 4000 drugs already approved by the Food and Drug Administration (FDA), we chose 14 shared compounds capable of recognizing three out of four sites. Finally, by means of visual inspection analysis and based on their commercial availability, five promising compounds were submitted to in vitro assays. Among them, PF-03715455 was able to block both the unwinding and NTPase activities of nsp13 in a micromolar range.

PMID:36364347 | DOI:10.3390/molecules27217522

Int J Mol Sci. 2022 Oct 26;23(21):12975. doi: 10.3390/ijms232112975.

ABSTRACT

Noise is a basic ingredient in data, since observed data are always contaminated by unwanted deviations, i.e., noise, which, in the case of overdetermined systems (with more data than model parameters), cause the corresponding linear system of equations to have an imperfect solution. In addition, in the case of highly underdetermined parameterization, noise can be absorbed by the model, generating spurious solutions. This is a very undesirable situation that might lead to incorrect conclusions. We presented mathematical formalism based on the inverse problem theory combined with artificial intelligence methodologies to perform an enhanced sampling of noisy biomedical data to improve the finding of meaningful solutions. Random sampling methods fail for high-dimensional biomedical problems. Sampling methods such as smart model parameterizations, forward surrogates, and parallel computing are better suited for such problems. We applied these methods to several important biomedical problems, such as phenotype prediction and a problem related to predicting the effects of protein mutations, i.e., if a given single residue mutation is neutral or deleterious, causing a disease. We also applied these methods to de novo drug discovery and drug repositioning (repurposing) through the enhanced exploration of huge chemical space. The purpose of these novel methods that address the problem of noise and uncertainty in biomedical data is to find new therapeutic solutions, perform drug repurposing, and accelerate and optimize drug discovery, thus reestablishing homeostasis. Finding the right target, the right compound, and the right patient are the three bottlenecks to running successful clinical trials from the correct analysis of preclinical models. Artificial intelligence can provide a solution to these problems, considering that the character of the data restricts the quality of the prediction, as in any modeling procedure in data analysis. The use of simple and plain methodologies is crucial to tackling these important and challenging problems, particularly drug repositioning/repurposing in rare diseases.

PMID:36361765 | DOI:10.3390/ijms232112975