創薬の指標（ver. 2023）

創薬化学の現場では、化合物最適化のための様々なパラメータが使われている。構造指標はその典型例で、リピンスキーの Ro5 などはよく知られている。古典的な考え方ではあるが、探索研究の現場でよく使われる実用的な指標で、化合物探索の生産性向上に貢献している。

最近では、学習データを使って機械学習モデルを構築、予測モデルを活用するアプローチが主流だと思う。とはいえ、古典的な経験則もやはり良いもので、実用性は高い（現実に役に立っているから生き残るわけで）。古典的な構造指標を説明変数として導入し、機械学習モデルを発展させることも当然可能である。

本エントリーでは低分子創薬でよく知られている古典的な指標について収集する（古い論文が多く、備忘録＆コレクション的な意味合いも）。

今年出た論文で面白かったのは、IQ WG と Arvinas が報告した「PROTAC の推奨レンジ」に関する報告。「PROTAC はこのくらいのレンジに収まっていないと、先に進めるのはちょっとシンドイですよ」という、一定のラインが見えてきたような印象。もちろん、重要なのは実験事実であり、構造指標よる判断はあくまで目安、指針の位置づけになるわけだが。

2023/4/11 (IQ WG)

Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders - PubMed

2023/6/6 (Arvinas)

Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders - PubMed

構造指標に関する洞察は、化合物を絞り込んだり、何をやらないかを決めたりする際に役立つ。「温故知新」「巨人の肩に乗る」ということで、柔軟に有効活用していきたい。

我々が古来からの伝統と思い込んでいる事柄とて、それが成された当初はすべてが新しかったのだ。

クラウディウス

今や知識とされるものは、それが知識であるということを、行為によって証明しなければならない。今日、われわれが知識とするものは、行動のための情報、成果に焦点を合わせた情報である。

ピーター・ドラッカー

※忘れているもの、見落としているものも多いと思います。適宜追加、整理、不定期に更新します。

Lipinski's rule / Rule of 5 (Ro5) / Drug-likeness

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings - PubMed

MedChem Mnemonic Rules: Lipinski’s RO5, RO3, bRO5, 3/75 Rule, ABS Score.

Extended Ro5 (eRo5) / Drug-likeness

Molecular properties that influence the oral bioavailability of drug candidates - PubMed

Beyond Ro5 (bRo5) / Drug-likeness

How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets - PubMed

Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates - PubMed

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

Veber's rule / Drug-Likeness

Molecular properties that influence the oral bioavailability of drug candidates - PubMed

Oprea's rule / Lead-likeness

Pursuing the leadlikeness concept in pharmaceutical research - PubMed

Ghose filter

A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases - PubMed

Muegge's rule

Selection criteria for drug-like compounds - PubMed

Rule of 4 (Ro4) / Lead-likeness

A 'rule of three' for fragment-based lead discovery? - PubMed

Rule of 3 (Ro3) / Fragment-likeness

A 'rule of three' for fragment-based lead discovery? - PubMed

Fragment-Based Drug Discovery：その概念と狙い

Rule of 2 (Ro2) / Building block

Designing novel building blocks is an overlooked strategy to improve compound quality - PubMed

QBB (Pfizer)

Quick Building Blocks (QBB): An Innovative and Efficient Business Model To Speed Medicinal Chemistry Analog Synthesis - PubMed

3/75 rule (Pfizer) / Drug-likeness

Physiochemical drug properties associated with in vivo toxicological outcomes - PubMed

Utility of Physicochemical Properties for the Prediction of Toxicological Outcomes: Takeda Perspective - PubMed

4/400 rule (GSK) / Drug-likeness

Generation of a set of simple, interpretable ADMET rules of thumb - PubMed

Golden Triangle (Pfizer) / Drug-likeness

Using the Golden Triangle to optimize clearance and oral absorption - PubMed

Molecular Weight

A comparison of physiochemical property profiles of development and marketed oral drugs - PubMed

Molecular Property Design: Does Everyone Get It? - PubMed

※分子量分布の参考

The normalized molecular weight distribution of our training dataset along with several drug and natural product libraries such as KEGG DRUG Database, DRUGBANK and Universal Natural Product Database (UNPD). (Figure 1, J. Lee et al., 2023)

LogP

Lipophilicity in drug discovery - PubMed

The influence of lipophilicity in drug discovery and design - PubMed

Calculation of molecular lipophilicity: State-of-the-art and comparison of log P methods on more than 96,000 compounds - PubMed

Partition Coefficient P (logP)

※logP の計算値
CLogP, ALogP, XLogP, MLogP, ALOGPS, LogP, QLogP, ELogP
CLogP や AlogP はよく使うが、いろいろな計算方法が研究されている
もちろん、機械学習モデルを組んで数値予測することも可

LogS

Prediction of drug solubility by the general solubility equation (GSE) - PubMed

ADME evaluation in drug discovery. 4. Prediction of aqueous solubility based on atom contribution approach - PubMed

SFI / Solubility Forecast Index

Getting physical in drug discovery: a contemporary perspective on solubility and hydrophobicity - PubMed

Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity - PubMed

HBA & HBD / H-Bond Acceptor & H-Bond Donor

Classification analysis of P-glycoprotein substrate specificity - PubMed

RB / Rotable Bond / 回転可能結合数

Molecular properties that influence the oral bioavailability of drug candidates - PubMed

NAR / 芳香環の数

The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types - PubMed

The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design? - PubMed

TPSA

Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties - PubMed

Molecular properties that influence the oral bioavailability of drug candidates - PubMed

Topological polar surface area: a useful descriptor in 2D-QSAR - PubMed

pKa / 酸解離定数

The pK(a) Distribution of Drugs: Application to Drug Discovery - PubMed

Fsp3

Escape from flatland: increasing saturation as an approach to improving clinical success - PubMed

Abbott Physicochemical Tiering (APT)--a unified approach to HTS triage - PubMed

LipE / Lipophilic efficiency / 脂溶性効率

Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis - PubMed

LE / Ligand efficiency / リガンド効率

Ligand efficiency: a useful metric for lead selection - PubMed

The role of ligand efficiency metrics in drug discovery - PubMed

Ligand efficiency as a guide in fragment hit selection and optimization - PubMed

BEI / Binding Efficiency Index / 結合効率指数

SEI / Surface-binding Efficiency Index / 表面結合効率指数

Ligand efficiency: a useful metric for lead selection - PubMed

ER / Eudismic ratio

Eudysmic ratio - Wikipedia

CNS / 中枢移行性

CNS Physicochemical Property Space Shaped by a Diverse Set of Molecules with Experimentally Determined Exposure in the Mouse Brain - PubMed

CNS drug design: balancing physicochemical properties for optimal brain exposure - PubMed

Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery - PubMed

CNS MedChem Mnemonic Rules: CNS bRO5, CNS MPO, pMPO, BBB Score.

QED / Quantitative Estimate of Drug-likeness

Drug discovery: Chemical beauty contest - PubMed

Quantifying the chemical beauty of drugs - PubMed

Biopharmaceutics Classification System (BCS)

Predicting drug disposition via application of BCS: transport/absorption/ elimination interplay and development of a biopharmaceutics drug disposition classification system - PubMed

Biopharmaceutics Classification System（BCS）に基づくバイオウェーバー～ガイドラインの解説と日本における課題～

P-gp

Classification analysis of P-glycoprotein substrate specificity - PubMed

CYP

Substrate SARs in human P450s - PubMed

チトクロムP-450の阻害に基づく薬物相互作用

チトクロムP-450を介した薬物代謝

創薬における薬物によるCYP誘導評価

Structural Alerts

Designing around Structural Alerts in Drug Discovery - PubMed

Bioactivation of Structural Alerts

The use of structural alerts to avoid the toxicity of pharmaceuticals - PubMed

PAINS / Pan-Assay Interference Compounds

Seven Year Itch: Pan-Assay Interference Compounds (PAINS) in 2017-Utility and Limitations - PubMed

Drug-likeness for PROTAC

Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders - PubMed

Physicochemical Property Determinants of Oral Absorption for PROTAC Protein Degraders - PubMed

FDA-approved Drug Library (SDFファイル)

FDA-approved Drug Library| 96/384-Well

FDA-approved Drug Library

フリーダウンロード（各社スクリーニング化合物データ） 医薬品と創薬化学品の専門商社 | ナミキ商事株式会社

総説、書籍など

Present drug-likeness filters in medicinal chemistry during the hit and lead optimization process: how far can they be simplified? - PubMed

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

Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization (English Edition)

Medicinal Chemistry for Practitioners