Dataset Information

Drug-like Properties and Fraction Lipophilicity Index as a combined metric.

ABSTRACT: Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log P and log D in a weighted manner. In the present study, an extended data set confirmed the previously established drug-like FLI range 0-8 using two calculation systems for log P/log D assessment, the freeware MedChem Designer and ClogP. The dataset was split into two classes according to the percentage of fraction absorbed (%FA) - class 1 including drugs with high to medium absorption levels and class 2 including poorly absorbed drugs. The FLI and FLI-C (ClogP based FLI) drug-like range covers 92 % and 91 % of class 1 drugs, respectively. Using MlogP, a narrower drug-like FLI-M range 0-7 was established, covering 91 % of class 1 drugs. The dependence of the degree of ionization to intrinsic lipophilicity within the FLI (FLI-C, FLI-M) drug-like range as well as the inter-relation between the other Ro5 properties (Mw, HD, HA) was explored to define drug-like / non-drug-like combinations as a safer alternative to single properties for drug candidates' prioritization. In this sense, we propose a combined metric of Mw and the number of polar atoms (Mw/NO) to account for both size and polarity. Setting the value 50 as cutoff, a distinct differentiation between class 1 and class 2 drugs was obtained with Mw/NO>50 for more than 70 % of class 1 drugs, while the opposite was observed for class 2 drugs.

SUBMITTER: Tsantili-Kakoulidou A

PROVIDER: S-EPMC8920096 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Drug-like Properties and Fraction Lipophilicity Index as a combined metric.

Tsantili-Kakoulidou Anna A Demopoulos Vassilis J VJ

ADMET & DMPK 20211010 3

Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log P and log D in a weighted manner. In the present study, an extended data set confirmed the previously established drug-like FLI range 0-8 using two calculation systems for log P/log D assessment, the freeware MedChem Designer and ClogP. The dataset was split into two classes according to the percentage of fraction absorbed (%FA) - class 1 including drugs with high to medi ...[more]

PMID: 35300360

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Project description:Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Spirometry loops are not smooth curves and have undulations and peaks that likely reflect heterogeneity of airflow.Objectives: To assess whether the Peak Index, the number of peaks adjusted for lung size, is associated with clinical outcomes.Methods: We analyzed spirometry data of 9,584 participants enrolled in the COPDGene study and counted the number of peaks in the descending part of the expiratory flow-volume curve from the peak expiratory flow to end-expiration. We adjusted the peaks count for the volume of the lungs from peak expiratory flow to end-expiration to derive the Peak Index. Multivariable regression analyses were performed to test associations between the Peak Index and lung function, respiratory morbidity, structural lung disease on computed tomography (CT), forced expiratory volume in 1 second (FEV1) decline, and mortality.Results: The Peak Index progressively increased from Global Initiative for Chronic Obstructive Lung Disease stage 0 through 4 (P < 0.001). On multivariable analysis, the Peak Index was significantly associated with CT emphysema (adjusted β = 0.906; 95% confidence interval [CI], 0.789 to 1.023; P < 0.001) and small airways disease (adjusted β = 1.367; 95% CI, 1.188 to 1.545; P < 0.001), St. George's Respiratory Questionnaire score (adjusted β = 1.075; 95% CI, 0.807 to 1.342; P < 0.001), 6-minute-walk distance (adjusted β = -1.993; 95% CI, -3.481 to -0.506; P < 0.001), and FEV1 change over time (adjusted β = -1.604; 95% CI, -2.691 to -0.516; P = 0.004), after adjustment for age, sex, race, body mass index, current smoking status, pack-years of smoking, and FEV1. The Peak Index was also associated with the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index and mortality (P < 0.001).Conclusions: The Peak Index is a spirometry metric that is associated with CT measures of lung disease, respiratory morbidity, lung function decline, and mortality.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Dataset Information

Drug-like Properties and Fraction Lipophilicity Index as a combined metric.

Publications

Drug-like Properties and Fraction Lipophilicity Index as a combined metric.

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