Medicinal Chemistry by the Numbers: The Physicochemistry, Thermodynamics and Kinetics of Modern Drug Design

Graham F. Smith    Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA

INTRODUCTION

At the beginning of my career as a medicinal chemist my job seemed to me more like a mysterious dark art than a science. It appeared then that the experienced medicinal chemists had a more intuitive approach rather than a rigorous scientific approach to finding active molecules. My training in synthetic chemistry taught what could be made, but it was hard to see what should be made, in the absence of knowledge of the target structure to enable structure-based drug design. More recently, a number of rules and equations based on scientific fact and precedent have been developed, and these promote good compound design and a statistically greater chance of successful drug development. In this chapter are outlined key aspects of modern physicochemistry, thermodynamics and kinetics which lead to good drug design. For an aspiring chemist, the ability to articulate the specific reasons for designing the features of compounds demonstrates a true mastery of the medicinal chemistry art.

It takes around 10 years to train a synthetic chemist to be a medicinal chemist and en route it is necessary to learn and understand many of these guidelines and why they are important. The description of the principles in this chapter, and their limitations, is intended to accelerate this training and lead to even better drug design.

Medicinal chemists have sometimes seemed to be sceptical of the predictions and rules. It is the view of this author that these guidelines are backed by scientific fact and evidence and therefore ignoring them can be folly.

PHYSICOCHEMISTRY

The landmark papers in the area of physicochemistry came over 10 years ago from Pfizer's Chris Lipinski [1, 2]. His analysis of 2,243 Phase II drug-like compounds from the USAN and INN (United States Adopted Name, International Non-proprietary Name) named drugs databases yielded a guideline, called the ‘rule of 5’, which has been widely adopted by those designing orally bioavailable drugs. Put simply, it states that 90% of all bioavailable drugs have molecular weight less than 500 or LogP less than 5 or fewer than 5 H-bond donors and fewer than 10 H-bond acceptors. Lipinski stated that ‘poor absorption is more likely if’ these physicochemical limits are surpassed, however many people reacted strongly initially focusing largely on exceptions to the rule rather than embracing the spirit of the analysis and conclusions. In the years that have followed though, physicochemistry has become a mainstay of modern drug discovery, as evidenced by the fact that Lipinski's original paper has been cited over 2,204 times [3] to date.

DRUG-LIKE MOLECULAR PROPERTIES

Drug-like – rule of 5

In the decade that has followed Lipinski's first publication, a deeper understanding of probabilities and causes of the physicochemical contribution to drug-likeness has led to the refinement of the rule of 5, most notably by workers at Pfizer, AstraZeneca and GSK. The rule of 5 has become deeply intuitive to medicinal chemists and they now routinely use either cLogP versus activity, or molecular weight versus activity, plots as principle components of compound design. In fact Gleeson [4] has shown that molecular weight and cLogP are the two principle components in discriminating drug-like physicochemical properties. Other researchers have added to and refined the rule of 5 still further. Veber et al.[5] and Pickett et al.[6] from GSK showed that it was possible to conclude that fewer than 10 rotatable bonds and polar surface area (PSA) of less than 140 Å2 were both related to better oral bioavailability. Kelder [7] and others showed that for CNS penetration the physicochemistry ranges were more tightly defined than for general oral bioavailability and that a lower value of PSA (less than 70 Å2) was important. Norinder and Haeberlein [8] have also shown that a more subtle balance of physicochemical properties, derived from (N+O) – LogP, must be positive to achieve a high probability of blood–brain barrier penetration.

Lead-like – rule of 4

Teague [9], Oprea [10] and Hann [11, 12] proposed that the physicochemistry of drug leads should be more tightly defined than the original rule of 5 to allow for the seemingly inevitable increase in the values of physicochemical parameters in the progression from leads to development candidates. Thus a rule of 4 for project leads from sources such as HTS can be defined (Table 1.1).

Fragment-like – rule of 3

In recent years, the pursuit of lead-like properties by screening very small molecules to find weakly active hits, but having high ligand efficiency, has become widely adopted. This has popularly become known as fragment-based drug discovery (FBDD) and is the subject of several recent high-quality reviews [14–17]. Congreve et al.[13] have defined a still tighter rule of 3 for molecules used as screening tools for FBDD which defines the smallest hit molecules that can be detected by specialist methods due to their low binding affinities.

These rules or guidelines now combine to signpost a sensible range of molecular weight and lipophilicity which should be tolerated at early stages of drug discovery. To go beyond these ranges at early stages of research when absorption, selectivity, toxicity and pharmacokinetics have yet to be addressed can easily lead to molecules that are non-optimisable at the later and more costly stages of pre-clinical research. Scheme 1.1 shows the well-known example of AT7519 (1) developed by Astex [18, 19] from a low molecular weight fragment (2). At each stage of its optimisation as a development candidate its properties obey the relevant rules from Table 1.1.

SHAPE

The classical view of medicinal chemistry is to work with the lock and key approach first postulated in 1894 by Emil Fischer. That is to say, design the small molecule key to fit the lock, which is the target enzyme or receptor. However, it is an oversimplification of both the lock and the key (target and receptor) to trust this analogy so far as to make important design decisions without confirmation by empirical means. René Magritte famously produced the picture ‘this is not a pipe’ (Figure 1.1). In the view of the author, medicinal chemists should hold this philosophical thought in mind when they use target structure to design small molecule inhibitors. Both protein and ligand are flexible objects that change shape dynamically under physiological conditions, and perhaps even more so when they interact with each other. So, any static picture of a protein does not robustly represent reality, as it does not usually show either the potential for movement or the multitude of water molecules that surround the protein or drug. Thus, very small differences in binding energy components, and flexibility in both the shape...