Bucket List 2019-05-15T14:25:40+00:00

Accelerating the life sciences ecosystem

MedChemica Bucket List

Accelerating the life sciences ecosystem

The MedChemica Bucket List.

The MedChemica Bucket List

BucketListPapers 6/100 : Standard Precision Glide (SP) – a step change in docking technology.

The paper presented an advance in docking technology that has been at the heart of Schrödinger’s software suite since. Standard Precision Glide (SP) is introduced in detail and includes terms for hydrophobic interactions, hydrogen bonds of charged and neutral types, metal interactions, a rotational bond penalty (for conformational entropy), coulombic and van der Waals terms.  In addition a solvation term considers water molecule presence. This glidescore is used to predict binding free energy and a combination of glidescore with molecular mechanics interaction energy and ligand strain energy to select docked poses. It is curious that it was necessary to scale the van der Waals’ radii (effectively shrink the atoms) to fit some known actives into their cognate binding sites. The effectiveness of the approach for correctly positioning ligands in the crystal structure they came from was compared to that with GOLD and FlexX. The test set used included those used for these other approaches and involved 282 complexes taken from crystal structures. To avoid bias from the ligand geometry, these were all created from scratch from 2D structures.

“Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy”  by Friesner, Banks, Murphy, Halgren, Klicic, Mainz, Repasky, Knoll, Shelley, Perry, Shaw, Francis and Shenken.

DOI: 10.1021/jm0306430

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BucketListPapers 5/100 : Lipinski – At number 5 The Rule of 5.

What else could be at number 5? In this article, the authors consider the properties that influence the solubility and permeability of drugs. This was partly a response to the introduction of high-throughput screening to drug discovery which yielded compounds that had never been tested in cells or in vivo and consequently had properties that need not be consistent with good solubility and permeability.  They showed that there had been an increase in higher molecular weight compounds and an increase in logP of compounds in the previous decade. The properties of a set of over 2000 drugs were considered (with a selection criteria for clinical exposure likely to favour orally bioavailable drugs).  Of these, about 10% was found to have a clogP above 5, about 11% a molecular weight above 500; such compounds are likely to have poor solubility.  A crude estimate of the number of hydrogen bond donors (number of OH + number of NH) and even cruder estimate of the number of acceptors (number of O + number of N) were also examined; only 8% of the drugs have donor count above 5 and only 12 % an acceptor count above 10.  These latter groups likely suffer from poor permeability. The period since this paper has seen a host of attempts to derive “rules” for other types of compounds (fragments, leads etc) although more nuanced views have also emerged.  Personally, we think that the prompt to consider the importance of solubility and permeability was a good one but the introduction of the idea of “rules” about what a drug looks like was a misstep.

“Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings” by Lipinski, Lombardo, Dominy and Feeney.


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BucketListPapers 4/100 : Optimising pKa – The kernel of an idea about molecular interactions

The sulphonamides exert their bacteriostatic effect by competing with p-aminobenzoic acid.  To gain a deeper understanding of the structure-activity relationship, the activity and pKa of 50 sulfonamides were measured.  This required measurements that were as free from confounding influences as possible – an approach that prefigured much of the work undertaken in target-based drug discovery using all the latest tools of molecular biology since the 1990s. It was found (see graph) that the sulphonamides show a maximum in activity at pKas around 6. This is explained by a requirement for the sulphonamide to be in its ionised form (as might be expected for competition with p-aminobenzoic acid) but that the anionic form must not see the charge so stabilised by delocalisation that the SO2 does not carry a maximal negative charge. These are the kernel of key ideas about understanding and optimising molecular interactions with a binding site that underpin much modern drug design.

“Studies in Chemotherapy. VII. A Theory of the Relation of Structure to Activity of Sulfanilamide Type Compounds” by Bell and Roblin  J. Am. Chem. Soc.(1942), 64, , 2905-2917

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BucketListPapers 3/100 : Hansch – Bringing Molecular Descriptors together

Various scientists had been gathering experimental data from which to extract descriptors that could be used to rationalise electronic (sigma values), size (molar refraction, MR and molecular weight, MW) and hydrophobic (pi values) effects caused by substituents, particularly on aromatic rings.  Hansch and co-workers aimed to bring all of these descriptors together in one place as a resource for those aiming to explore quantitative structure-activity relationships; an example of 4 groups that span the different types (polar vs hydrophobic, electron-donating vs withdrawing) is shown in the table.  Hansch et al.’s compilation of values remains a good starting point to understand the effects that various substituent types can exert, although Hansch and Leo went on to compile an even more comprehensive set: https://pubs.acs.org/doi/abs/10.1021/jm950902o. Some of our own work in matched molecular pairs has seen us effectively computing analogous values for the effect of aromatic substituents on solubility, plasma protein binding and other properties:  https://pubs.acs.org/doi/10.1021/jm0605233


Group Pi Sigma(meta) Sigma(para) MR MW
Me +0.56 -0.07 -0.17 5.65 15.0
F +0.14 +0.34 +0.06 0.92 19.0
NH2 -1.23 -0.16 -0.66 5.42 16.0
NO2 -0.28 +0.71 +0.78 7.36 46


“Aromatic Substituent Constants for Structure-Activity Correlations” by Hansch, Leo, Unger, Kim, Nikaitani and Lien.

DOI: 10.1021/jm00269a003


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BucketListPapers 2/100 – Free / Wilson asks “have we made the best combination of substituents yet?”

In this paper Free and Wilson analyse the variation in biological activity caused by substituents at various positions in a series of molecules.  They apply a simple least squares fitting to attribute a contribution that each substituent is making to the observed activity. This analysis of variance has become a fundamental tool for medicinal chemistry.  It is assumed that the SAR is additive although the possibility of additive and non-additive groups is discussed. The method should always be considered whenever the question is asked “have we made the best combination of substituents yet?” and as such should be used in almost every drug discovery project.  Recent developments building on the Free and Wilson approach have explored how many compounds must be included in the data set to ensure satisfactory values for the contributions of each group, for example:

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“A Mathematical Contribution to Structure-Activity Studies” by Free and Wilson. DOI:10.1021/jm00334a001

BucketListPapers 1/100 : The First Hint that Lipophilicity might be important….

Our first BucketListPaper is from 1899 and introduced the idea that the activity of anesthetics might correlate with  lipophilicity (as measured by partition into oil from water).  This first hint that lipophilicity might be a key property, as found by Overton and Meyer, kick-started the field of QSAR. The papers formed the basis of a theory of anesthesia, which still intrigues and stimulates new scientific studies.

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  1. Overton E. Studien über die Narkose Zugleich ein Beitrag zur Allgemeinen Pharmakologie. Jena, Germany: Verlag von Gustav Fisher, 1901. Meyer H. Zur Theorie der Alkoholnarkose. Arch Exp Pathol Pharmakol 1899;42: 109-18
  2. Graph abstracted by Campagna et al.: https://www.nejm.org/doi/full/10.1056/NEJMra021261)