STOPLIGHT: A Hit Scoring Calculator

Wellnitz, James; Martin, Holli-Joi; Anwar Hossain, Mohammad; Rath, Marielle; Fox, Colton; Popov, Konstantin I.; Willson, Timothy M.; Muratov, Eugene N.; Tropsha, Alexander

doi:10.1021/acs.jcim.4c00412

J. Chem. Inf. Model.

2024

DOI: 10.1021/acs.jcim.4c00412

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STOPLIGHT: A Hit Scoring Calculator

James Wellnitz,

Holli-Joi Martin,

Mohammad Anwar Hossain

et al.

Abstract: We introduce STOPLIGHT, a web portal to assist medicinal chemists in prioritizing hits from screening campaigns and the selection of compounds for optimization. STOPLIGHT incorporates services to assess 6 physiochemical and structural properties, 6 assay liabilities, and 11 pharmacokinetic properties, for any small molecule represented by its SMILES string. We briefly describe each service and illustrate the utility of this portal with a case study.The STOPLIGHT portal provides a user-friendly tool to guide hi… Show more

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Cited by 2 publications

References 24 publications

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Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

Andrade Meirelles,

Almeida,

Sullivan

et al. 2024

J. Med. Chem.

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Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

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Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

Andrade Meirelles,

Almeida,

Sullivan

et al. 2024

J. Med. Chem.

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Establishing a Pharmacoinformatics Repository of Approved Medicines: A Database to Support Drug Product Development

Murray,

Bennett-Lenane,

O’Dwyer

et al. 2024

Mol. Pharmaceutics

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Advanced predictive modeling approaches have harnessed data to fuel important innovations at all stages of drug development. However, the need for a machine-readable drug product library which consolidates many aspects of formulation design and performance remains largely unmet. This study presents a scripted, reproducible approach to database curation and explores its potential to streamline oral medicine development. The Product Information files for all centrally authorized drug products containing a small molecule active ingredient were retrieved programmatically from the European Medicines Agency Web site. Text processing isolated relevant information, including the maximum clinical dose, dosage form, route of administration, excipients, and pharmacokinetic performance. Chemical and bioactivity data were integrated through automated linking to external curated databases. The capability of this database to inform oral medicine development was assessed in the context of drug-likeness evaluation, excipient selection, and prediction of oral fraction absorbed. Existing filters of drug-likeness, such as the Rule of Five, were found to poorly capture the chemical space of marketed oral drug products. Association rule learning identified frequent patterns in tablet formulation compositions that can be used to establish excipient combinations that have seen clinical success. Binary prediction models of oral fraction absorbed constructed exclusively from regulatory data achieved acceptable performance (balanced accuracy test = 0.725), demonstrating its modelability and potential for use during early stage molecule prioritization tasks. This study illustrates the impact of highly linked drug product data in accelerating clinical translation and underlines the ongoing need for accuracy and completeness of data reported in the regulatory datasphere.

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STOPLIGHT: A Hit Scoring Calculator

Cited by 2 publications

References 24 publications

Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

Establishing a Pharmacoinformatics Repository of Approved Medicines: A Database to Support Drug Product Development

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