Tight binding enantiomers of pre-clinical drug candidates

According to WHO report, globally about 10 million active tuberculosis cases, resulting in about 1.6 million deaths, further aggravated by drug-resistant tuberculosis and/or comorbidities with HIV and diabetes are present. Incomplete therapeutic regimen, meager dosing, and the capability of the latent and/or active state tubercular bacilli to abide and do survive against contemporary first-line and second line antitubercular drugs escalate the prevalence of drug-resistant tuberculosis. As a better understanding of tuberculosis, microanatomy has discovered an extended range of new promising antitubercular targets and diagnostic biomarkers. However, there are still no new approved antitubercular drugs of routine therapy for several decades, except for bedaquiline, delamanid, and pretomanid approved tentatively. Despite this, innovative methods are also urgently needed to find potential new antitubercular drug candidates, which potentially decimate both latent state and active state mycobacterium tuberculosis. To explore and identify the most potential antitubercular drug candidate among various reported compounds, we focused to highlight the promising lead derivatives of isoniazid, coumarin, griselimycin, and the antimicrobial peptides. The aim of the present review is to fascinate significant lead compounds in the development of potential clinical drug candidates that might be more precise and effective against drug-resistant tuberculosis, the world research looking for a long time.

Download Full-text

IN VITRO P-GLYCOPROTEIN INHIBITION ASSAYS FOR ASSESSMENT OF CLINICAL DRUG INTERACTION POTENTIAL OF NEW DRUG CANDIDATES: A RECOMMENDATION FOR PROBE SUBSTRATES

Drug Metabolism and Disposition ◽

10.1124/dmd.105.008615 ◽

2006 ◽

Vol 34 (5) ◽

pp. 786-792 ◽

Cited By ~ 189

Author(s):

Jarkko Rautio ◽

Joan E. Humphreys ◽

Lindsey O. Webster ◽

Anand Balakrishnan ◽

John P. Keogh ◽

...

Keyword(s):

Drug Interaction ◽

Interaction Potential ◽

Drug Candidates ◽

New Drug ◽

P Glycoprotein ◽

Glycoprotein Inhibition ◽

Clinical Drug

Download Full-text

Structure of mycobacterial cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates

10.1101/2021.06.15.448498 ◽

2021 ◽

Author(s):

Shan Zhou ◽

Weiwei Wang ◽

Xiaoting Zhou ◽

Yuying Zhang ◽

Yuezheng Lai ◽

...

Keyword(s):

Electron Microscopy ◽

High Resolution ◽

Structural Information ◽

Mycobacterial Infections ◽

Drug Candidates ◽

Cryo Electron Microscopy ◽

Antibiotic Drug ◽

Binding Pockets ◽

Quinol Binding ◽

Clinical Drug

Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome bcc complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome bcc complex from these pathogenic mycobacteria. Here, we report the structures of M. tuberculosis cytochrome bcc alone (2.68 Å resolution) and in complex with clinical drug candidates Q203 (2.67 Å resolution) and TB47 (2.93 Å resolution) determined by single-particle cryo-electron microscopy. M. tuberculosis cytochrome bcc forms a dimeric assembly with endogenous menaquinone/menaquinol bound at the quinone/quinol binding pockets. Q203 and TB47 are bound to the quinol-binding site. Hydrogen bonds are formed between the inhibitor and the side chains of QcrBThr313 and QcrBGlu314, residues that are conserved across pathogenic mycobacteria. These high-resolution structures provide a basis for the design of new mycobacterial cytochrome bcc inhibitors that could be developed into broad spectrum drugs to treat mycobacterial infections.

Download Full-text

COVID-KOP: Integrating Emerging COVID-19 Data with the ROBOKOP Database

10.26434/chemrxiv.12462623.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Daniel Korn ◽

Tesia Bobrowski ◽

Michael Li ◽

Yaphet Kebede ◽

Patrick Wang ◽

...

Keyword(s):

Biomedical Literature ◽

Knowledge Graph ◽

Biomedical Knowledge ◽

Drug Candidates ◽

Clinical Drug

<p>In response to the COVID-19 pandemic, we established COVID-KOP, a new knowledgebase integrating the existing ROBOKOP biomedical knowledge graph with information from recent biomedical literature on COVID-19 annotated in the CORD-19 collection. COVID-KOP can be used effectively to test new hypotheses concerning repurposing of known drugs and clinical drug candidates against COVID-19. COVID-KOP is freely accessible at <a href="https://covidkop.renci.org/">https://covidkop.renci.org/</a>. For code and instructions for the original ROBOKOP, see: https://github.com/NCATS-Gamma/robokop.</p>

Download Full-text

SSC-ILD mouse model induced by osmotic minipump delivered bleomycin: effect of Nintedanib

Scientific Reports ◽

10.1038/s41598-021-97728-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Francesca Ravanetti ◽

Erica Ferrini ◽

Luisa Ragionieri ◽

Zahra Khalajzeyqami ◽

Maria Nicastro ◽

...

Keyword(s):

Lung Fibrosis ◽

Integrative Approach ◽

Micro Ct ◽

Reference Compound ◽

Internal Organs ◽

Drug Candidates ◽

Fibrosis Progression ◽

Ct Analysis ◽

Clinical Drug ◽

Selection Of

AbstractSystemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). Its pathogenetic mechanisms are unknown and the lack of animal models mimicking the features of the human disease is creating a gap between the selection of anti-fibrotic drug candidates and effective therapies. In this work, we intended to pharmacologically validate a SSc-ILD model based on 1 week infusion of bleomycin (BLM) by osmotic minipumps in C57/BL6 mice, since it will serve as a tool for secondary drug screening. Nintedanib (NINT) has been used as a reference compound to investigate antifibrotic activity either for lung or skin fibrosis. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, which was confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported here could reflect the clinical outcome, highlighting the reliability of this model to better profile potential clinical drug candidates. The integrative approach presented herein, which combines longitudinal assessments with endpoint analyses, could be harnessed in drug discovery to generate more reliable, reproducible and robust readouts.

Download Full-text

Rapid Identification and Validation of Novel Rheumatoid Arthritis Drug Treatments using an Integrative Bioinformatics Platform

10.1101/243998 ◽

2018 ◽

Author(s):

Aaron C. Daugherty ◽

Carl Farrington ◽

Isaac Hakim ◽

Sana Mujahid ◽

Elizabeth S. Noblin ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Therapeutic Targets ◽

Rapid Identification ◽

Data Types ◽

Drug Candidates ◽

Disease Associations ◽

Future Drug ◽

Drug Treatments ◽

Clinical Drug

AbstractThe majority of drugs currently used to treat rheumatoid arthritis (RA) act on a small number of immunomodulatory targets. We applied an integrative biomedical-informatics-based approach and in vivo testing to identify new drug candidates and potential therapeutic targets that could form the basis for future drug development in RA. A computational model of RA was constructed by integrating patient gene expression data, molecular interactions, and clinical drug-disease associations. Drug candidates were scored based on their predicted efficacy across these data types. Ten high-scoring candidates were subsequently screened in a collagen-induced arthritis model of RA. Treatment with exenatide, olopatadine, and TXR-112 significantly improved multiple preclinical endpoints, including animal mobility which was measured using a novel digital platform. These three drug candidates do not act on common RA therapeutic targets; however, links between known candidate pharmacology and pathological processes involved in RA suggest hypothetical mechanisms contributing to the observed efficacy.

Download Full-text

The trypanosome alternative oxidase: a potential drug target?

Parasitology ◽

10.1017/s0031182016002109 ◽

2016 ◽

Vol 145 (2) ◽

pp. 175-183 ◽

Cited By ~ 18

Author(s):

STEFANIE K. MENZIES ◽

LINDSAY B. TULLOCH ◽

GORDON J. FLORENCE ◽

TERRY K. SMITH

Keyword(s):

Drug Target ◽

Alternative Oxidase ◽

Mitochondrial Protein ◽

New Drugs ◽

Drug Candidates ◽

Mammalian Mitochondria ◽

And Function ◽

Trypanosome Alternative Oxidase ◽

Clinical Drug

SUMMARYNew drugs against Trypanosoma brucei, the causative agent of Human African Trypanosomiasis, are urgently needed to replace the highly toxic and largely ineffective therapies currently used. The trypanosome alternative oxidase (TAO) is an essential and unique mitochondrial protein in these parasites and is absent from mammalian mitochondria, making it an attractive drug target. The structure and function of the protein are now well characterized, with several inhibitors reported in the literature, which show potential as clinical drug candidates. In this review, we provide an update on the functional activity and structural aspects of TAO. We then discuss TAO inhibitors reported to date, problems encountered with in vivo testing of these compounds, and discuss the future of TAO as a therapeutic target.

Download Full-text

Development of Novel, 384-Well High-Throughput Assay Panels for Human Drug Transporters

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057113494807 ◽

2013 ◽

Vol 18 (9) ◽

pp. 1072-1083 ◽

Cited By ~ 12

Author(s):

Huaping Tang ◽

Ding Ren Shen ◽

Yong-Hae Han ◽

Yan Kong ◽

Praveen Balimane ◽

...

Keyword(s):

High Throughput ◽

Critical Role ◽

Regulatory Agencies ◽

Functional Assay ◽

Regulatory Requirements ◽

Drug Candidates ◽

Efflux Inhibition ◽

Hepatobiliary Disposition ◽

High Throughput Assay ◽

Clinical Drug

Transporter proteins are known to play a critical role in affecting the overall absorption, distribution, metabolism, and excretion characteristics of drug candidates. In addition to efflux transporters (P-gp, BCRP, MRP2, etc.) that limit absorption, there has been a renewed interest in influx transporters at the renal (OATs, OCTs) and hepatic (OATPs, BSEP, NTCP, etc.) organ level that can cause significant clinical drug-drug interactions (DDIs). Several of these transporters are also critical for hepatobiliary disposition of bilirubin and bile acid/salts, and their inhibition is directly implicated in hepatic toxicities. Regulatory agencies took action to address transporter-mediated DDI with the goal of ensuring drug safety in the clinic and on the market. To meet regulatory requirements, advanced bioassay technology and automation solutions were implemented for high-throughput transporter screening to provide structure-activity relationship within lead optimization. To enhance capacity, several functional assay formats were miniaturized to 384-well throughput including novel fluorescence-based uptake and efflux inhibition assays using high-content image analysis as well as cell-based radioactive uptake and vesicle-based efflux inhibition assays. This high-throughput capability enabled a paradigm shift from studying transporter-related issues in the development space to identifying and dialing out these concerns early on in discovery for enhanced mechanism-based efficacy while circumventing DDIs and transporter toxicities.

Download Full-text

Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates

eLife ◽

10.7554/elife.69418 ◽

2021 ◽

Vol 10 ◽

Author(s):

Shan Zhou ◽

Weiwei Wang ◽

Xiaoting Zhou ◽

Yuying Zhang ◽

Yuezheng Lai ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Structural Information ◽

Mycobacterial Infections ◽

Drug Candidates ◽

Cryo Electron Microscopy ◽

Antibiotic Drug ◽

Binding Pockets ◽

High Resolution Images ◽

Quinol Binding ◽

Clinical Drug

Pathogenic mycobacteria pose a sustained threat to global human health. Recently, cytochrome bcc complexes have gained interest as targets for antibiotic drug development. However, there is currently no structural information for the cytochrome bcc complex from these pathogenic mycobacteria. Here, we report the structures of Mycobacterium tuberculosis cytochrome bcc alone (2.68 Å resolution) and in complex with clinical drug candidates Q203 (2.67 Å resolution) and TB47 (2.93 Å resolution) determined by single-particle cryo-electron microscopy. M. tuberculosis cytochrome bcc forms a dimeric assembly with endogenous menaquinone/menaquinol bound at the quinone/quinol-binding pockets. We observe Q203 and TB47 bound at the quinol-binding site and stabilized by hydrogen bonds with the side chains of QcrBThr313 and QcrBGlu314, residues that are conserved across pathogenic mycobacteria. These high-resolution images provide a basis for the design of new mycobacterial cytochrome bcc inhibitors that could be developed into broad-spectrum drugs to treat mycobacterial infections.

Download Full-text