Some thoughts on pharmaceutical molecular design

Peter W Kenny

NEQUIMED-IQSC-USP

Some things that make drug design difficult

• Having to exploit targets that are weakly-linked to

human disease

• Poor understanding and prediction of toxicity

• Inability to measure free (unbound) physiological

concentrations of drug for remote targets (e.g.

intracellular or on far side of blood brain barrier)

Dans la merde http://fbdd-lit.blogspot.com/2011/09/dans-la-merde.html

Molecular Design

• Control of behavior of compounds and materials by

manipulation of molecular properties

• Hypothesis-driven or prediction-driven

• Sampling of chemical space

– For example, does fragment-based screening allow better

control of sampling resolution?

Kenny, Montanari, Propopczyk, Sala, Sartori (2013) JCAMD 27:655-664 DOI

Kenny JCIM 2009 49:1234-1244 DOI

Hypothesis-driven Molecular Design

• Ask good questions with informative compounds and

relevant assays

• Framework for establishing structure-activity

relationships (SARs) as efficiently as possible

• Molecular interactions provide natural framework in

which to pose design hypotheses

Kenny JCIM 2009 49:1234-1244 DOI Hypothesis-driven design versus prediction driven molecular design

Linusson et al JMC 2000 43:1320-1328 DOI Statistical molecular design

Bissantz, Kuhn & Stahl JMC 2010 53:5061-5084 DOI Medicinal chemist’s guide to molecular interactions

TEP = [𝐷𝑟𝑢𝑔 𝑿,𝑡 ]𝑓𝑟𝑒𝑒

𝐾𝑑

Target engagement potential (TEP)

A basis for pharmaceutical molecular design?

Design objectives

• Low Kd for target(s)

• High (hopefully undetectable) Kd for antitargets

• Ability to control [Drug(X,t)]free

Kenny, Leitão & Montanari JCAMD 2014 28:699-710 DOI

Property-based design as search for ‘sweet spot’

Green and red lines represent probability of achieving ‘satisfactory’ affinity and

‘satisfactory’ ADMET characteristics respectively. The blue line shows the product of

these probabilities and characterizes the ‘sweet spot’. This way of thinking about the

‘sweet spot’ has similarities with Hann molecular complexity model

Kenny & Montanari, JCAMD 2013 27:1-13 DOI

Structures of protein-ligand complexes in medicinal

chemistry

• Fragment screening

• Confirmation that ‘actives’ do actually bind

• Binding mode as framework for design hypotheses

and predictive models

– Intermolecular contacts

• Beware of ligand efficiency metrics and remember that the contribution

of a contact (or group of contacts) to affinity is not, in general, an

experimental observable

– Conformations

– Ionisation states

– Tautomers

PTP1B (Diabetes/Obesity): Fragment elaboration

Literature SAR was mapped onto intial fragment hit (green). Note overlay of

aromatic rings of elaborated fragment (blue) and difluorophosphonate (red).

Black et al BMCL 2005 15:2503-2507 DOI

Inactive at 200mM

15 mM

3000 mM3 mM

150 mM

(Conformational lock)

130 mM

(3-Phenyl substituent)

Stuff to think about

• Molecular design is not just about prediction

• Binding of ligands in high energy forms (e.g.

conformational, protonation, tautomeric) should

always be seen as design opportunity