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Towards holistic Compound Quality Scores: Extending ligand efficiency indices with compound pharmacokinetic characteristics

DRUG DISCOVERY TODAY (2023)

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Computational Predictions of Nonclinical Pharmacokinetics at the Drug Design Stage

Raya Stoyanova et al.

Summary: This study used a dataset of mouse and rat PK studies at Roche to predict PK properties, such as plasma clearance (CLp), volume of distribution at steady-state (Vss), and oral bioavailability (F), using chemical structure alone. The results showed that AutoGluon, Gaussian Process Regressor (GP), and ChemProp had the best performance. Various methods, such as prediction variance, molecular clustering, and dimensionality-reduction, provided valuable insights into prediction uncertainty and applicability domains. SHAPley Additive exPlanations (SHAPs) highlighted molecular features contributing to the prediction outcomes of Vss, providing explanations for drug design.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2023)

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Editorial Material Chemistry, Multidisciplinary

Rules were made to be broken

Ingo V. Hartung et al.

Summary: The 'rule of 5' has been a highly influential sentence in small-molecule drug discovery for the past twenty five years, shaping the work of medicinal chemists. However, its relevance in today's medicinal chemistry efforts is being questioned.

NATURE REVIEWS CHEMISTRY (2023)

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Article Biochemistry & Molecular Biology

Artificial intelligence in multi-objective drug design

Sohvi Luukkonen et al.

Summary: The factors determining a drug's success are diverse, making drug design a multi-objective optimisation problem. With the emergence of machine learning and optimisation methods, there has been a rapid increase in developments and applications in the field of multi-objective compound design. Population-based metaheuristics and deep reinforcement learning are commonly used methods, but conditional learning methods are gaining popularity. This article provides a brief overview of the field and the latest innovations.

CURRENT OPINION IN STRUCTURAL BIOLOGY (2023)

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Article Chemistry, Medicinal

Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection

Daniel H. O' Donovan et al.

Summary: Medicinal chemists aim to design oral drugs with high oral bioavailability, and permeability is a key factor. By studying >2000 compounds tested in rat bioavailability studies and >20,000 compounds tested in Caco2 assays at Bayer, the molecular properties governing bioavailability and permeability have been examined. Besides classical parameters like logD and molecular weight, the relationship between calculated pKa and permeability has also been investigated. Design guidelines for bioavailable drugs in both traditional and beyond rule of 5 (bRo5) chemical space are provided based on these property-structure relationships.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

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Article Chemistry, Medicinal

ADMET Predictability at Boehringer Ingelheim: State-of-the-Art, and Do Bigger Datasets or Algorithms Make a Difference?

Stevan Aleksic et al.

Summary: Despite the widespread use of computational methods in drug discovery and development in the pharmaceutical industry, our study found that there is no significant impact on prediction from data volume, modeling algorithm, chemical representation and grouping, and temporal aspect relationships.

MOLECULAR INFORMATICS (2022)

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Article Chemistry, Medicinal

25 Years of Small-Molecule Optimization at Novartis: A Retrospective Analysis of Chemical Series Evolution

Maximilian Beckers et al.

Summary: In the process of drug development, optimizing the properties and biological activities of small molecules is crucial. This study retrospectively reconstructed around 3000 chemical series to characterize their properties and the evolution of structural properties, ADMET properties, and target activities. The findings suggest that during the optimization process, the size, sp3-hybridized carbon atoms, and stereocenter density of compounds tend to increase, while aromaticity decreases. Solubility tends to increase, permeability decreases, and safety-related properties improve. Importantly, target activities and lipophilic efficiency tend to improve over time.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2022)

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Article Chemistry, Medicinal

LipMetE (Lipophilic Metabolism Efficiency) as a Simple Guide for Half-Life and Dosing Regimen Prediction of Oral Drugs

Giuseppe Cecere et al.

Summary: The in vivo half-life is a crucial property of drug molecules, influencing dosing regimens and dosage. The use of Lipophilic Metabolism Efficiency (LipMetE) as a medicinal chemistry design parameter simplifies half-life optimization for neutral and basic compounds, enabling rational drug discovery projects.

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Maria Korshunova et al.

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COMMUNICATIONS CHEMISTRY (2022)

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Review Pharmacology & Pharmacy

Ligand efficiency indices for effective drug discovery: a unifying vector formulation

Celerino Abad-Zapatero

Summary: The field of ligand efficiency indices (LEIs) in drug discovery has evolved significantly over the past two decades, with various LEIs defined and applied to a certain degree of success and acceptance in the community. This review emphasizes the numerical and algebraic relationships among different LEIs and introduces the concept of 'ligand efficiency index' (LEI) as a vector variable with two interrelated components to provide direction and distance in the drug discovery process. The extension of ligand efficiency from a scalar to a vector is proposed to unify different formulations and emphasize the relationship among variables, offering a robust framework to assess the value of LEIs and incorporate them into workflows and protocols in drug discovery. Rigorous testing by the community is needed to determine the possible value of LEIs as reliable optimization variables.

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Article Chemistry, Medicinal

Target-Based Evaluation of Drug-Like Properties and Ligand Efficiencies

Paul D. Leeson et al.

Summary: The study compares the physicochemical properties of drugs approved between 2010-2020 with compounds reported to bind to their efficacious target. It finds that drugs differ from their target comparators in terms of potency, ligand efficiency, and other descriptors. Furthermore, 96% of drugs have values of LE or LLE greater than the median values of their target comparator compounds.

JOURNAL OF MEDICINAL CHEMISTRY (2021)

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Article Chemistry, Medicinal

Holistic drug design for multiparameter optimization in modern small molecule drug discovery

Lewis D. Pennington et al.

Summary: Modern small molecule drug discovery requires holistic drug design for multiparameter optimization, strategically using multiple drug design approaches based on the goal and stage of the drug discovery program, the quantity and quality of data for analyses, and the availability and accuracy of predictive models to increase the efficiency and success rate of small molecule drug discovery.

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Prediction of active human dose: learnings from 20 years of Merck KGaA experience, illustrated by case studies

Sheila Annie Peters et al.

DRUG DISCOVERY TODAY (2020)

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Petra Schneider et al.

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Minimal-uncertainty prediction of general drug-likeness based on Bayesian neural networks

Wiktor Beker et al.

NATURE MACHINE INTELLIGENCE (2020)

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Article Chemistry, Multidisciplinary

The nature of ligand efficiency

Peter W. Kenny

JOURNAL OF CHEMINFORMATICS (2019)

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Review Pharmacology & Pharmacy

Estimating human ADME properties, pharmacokinetic parameters and likely clinical dose in drug discovery

Adam J. Lucas et al.

EXPERT OPINION ON DRUG DISCOVERY (2019)

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Article Chemistry, Medicinal

Prediction of Oral Bioavailability in Rats: Transferring Insights from in Vitro Correlations to (Deep) Machine Learning Models Using in Silico Model Outputs and Chemical Structure Parameters

Sebastian Schneckener et al.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2019)

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Article Chemistry, Medicinal

Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection

David A. DeGoey et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Biochemistry & Molecular Biology

Practical application of ligand efficiency metrics in lead optimisation

James S. Scott et al.

BIOORGANIC & MEDICINAL CHEMISTRY (2018)

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Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations

Robert J. Young et al.

JOURNAL OF MEDICINAL CHEMISTRY (2018)

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Article Chemistry, Medicinal

Strategy for Extending Half-life in Drug Design and Its Significance

Hakan Gunaydin et al.

ACS MEDICINAL CHEMISTRY LETTERS (2018)

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Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery

Travis T. Wager et al.

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Quality guidelines for oral drug candidates: dose, solubility and lipophilicity

Martin K. Bayliss et al.

DRUG DISCOVERY TODAY (2016)

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Automatically updating predictive modeling workflows support decision-making in drug design

Ingo Muegge et al.

FUTURE MEDICINAL CHEMISTRY (2016)

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Editorial Material Chemistry, Medicinal

Molecular Property Design: Does Everyone Get It?

Paul D. Leeson et al.

ACS MEDICINAL CHEMISTRY LETTERS (2015)

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Article Biochemistry & Molecular Biology

Ligand efficiency metrics considered harmful

Peter W. Kenny et al.

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN (2014)

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Article Biotechnology & Applied Microbiology

The role of ligand efficiency metrics in drug discovery

Andrew L. Hopkins et al.

NATURE REVIEWS DRUG DISCOVERY (2014)

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Article Chemistry, Medicinal

The thermodynamic basis for the use of lipophilic efficiency (LipE) in enthalpic optimizations

Michael D. Shultz

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2013)

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Article Chemistry, Medicinal

Evaluating the Differences in Cycloalkyl Ether Metabolism Using the Design Parameter Lipophilic Metabolism Efficiency (LipMetE) and a Matched Molecular Pairs Analysis

Antonia F. Stepan et al.

JOURNAL OF MEDICINAL CHEMISTRY (2013)

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Article Chemistry, Multidisciplinary

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G. Richard Bickerton et al.

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Assessing the lipophilicity of fragments and early hits

Paul N. Mortenson et al.

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN (2011)

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Article Chemistry, Medicinal

Time-Trajectories in Efficiency Maps as Effective Guides for Drug Discovery Efforts

Serge Christmann-Franck et al.

MOLECULAR INFORMATICS (2011)

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Article Biotechnology & Applied Microbiology

Probing the links between in vitro potency, ADMET and physicochemical parameters

M. Paul Gleeson et al.

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Article Chemistry, Medicinal

An Analysis of the Binding Efficiencies of Drugs and Their Leads in Successful Drug Discovery Programs

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JOURNAL OF MEDICINAL CHEMISTRY (2010)

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Article Chemistry, Medicinal

Simple Size-Independent Measure of Ligand Efficiency

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The influence of drug-like concepts on decision-making in medicinal chemistry

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Drug-like properties and the causes of poor solubility and poor permeability

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