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Overview of Hit to Lead: The Medicinal Chemist's Role from HTS Retest to Lead Optimization Hand Off

  • Christopher A. LipinskiEmail author
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 5)

Abstract

A medicinal chemist combines organic synthesis expertise and the ability to optimize chemistry structure-activity relationships (SAR) based on relevant biomedical information so as to achieve project goals. The ability to optimize chemistry SAR consists of both the easier to explain logical stepwise structural modification that is often described by quantitative structure-activity relationships (QSAR) and the more difficult to explain exercise of high-order pattern recognition. Optimizing SAR is full of traps for the unwary. What are the pros and cons of various types of screens  Should one believe the screening data  How does one optimize against multiple sometimes conflicting properties  What types of compounds are worth screening  How does one judge the quality of a screening hit  Very importantly, drug discovery is a team exercise in which the medicinal chemist plays a key facilitating role. Given good interpersonal skills, the medicinal chemist's training is broad enough to enable cooperative interactions across the whole discovery team. Chemistry pattern recognition is the unique skill that the medicinal chemist contributes to drug discovery. The ability to relate chemistry structure to biological activity and to change chemistry structure so as to change a variety of biomedical parameters in a desired direction leads to the successful “drug hunter.”

Keywords

HTS Hit to lead Medicinal chemistry Pattern recognition Screening 

Abbreviations and Symbols

<

Less than

>

Greater than

ADMET

Absorbance distribution metabolism excretion toxicity

Apo structure

Structure of a protein without a bound ligand

ATP

Adenosine triphosphate

Cherry pick

Individually selecting a screening sample from a larger set

CLND

Chemi luminescent nitrogen detector

CNS

Central nervous system

DMSO

Dimethylsulfoxide

DNA

Deoxy ribonucleic acid

DOS

Diversity-oriented synthesis

GPCR

G-protein coupled receptor

H-bond

Hydrogen bond

HERG

Human ether-a-go–go related gene

HIV

Human immunodifficiency virus

HPLC

High performance liquid chromatography

HTS

High throughput screening

IC50

Inhibitory concentration (at) 50% inhibition

IP

Intellectual property

kg

Kilogram

L

Liter

Log P

Logarithm (base 10) of P (Partition coefficient)

MDR1

Multidrug resistant (Gene) 1

mg

Milligram

mL

Milliliter

mM

Millimolar

MS

Mass spectrum

MWT

Molecular weight

NDA

New drug application

NIH

National institutes of health

nM

Nanomolar

NMR

Nuclear magnetic resonance

NSAI

Non steroidal anti inflammatory

P

Partition coefficient (of drug) between normal octanol and water

PCR

Polymerase chain reaction

PDE

Phospho diesterase

pK/pD

Pharmacokinetics/pharmacodynamics

QSAR

Quantitative structure – activity relationship

RO5

Rule of 5

SAR

Structure – activity relationship

sdf

Structure data file

SiRNA

Short intervening ribonucleic acid

SPR

Surface plasmon resonance

µM

Micromolar

z′

HTS quality criterion based on positive and negative compound controls

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Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Scientific Advisor, Melior DiscoveryWaterfordUSA

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