Literature
1. “Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings”, Lipinski et al., DOI
I guess this could be considered the grand-daddy of them all. Often cited, often mis-understood. Well worth reading. Again.
2. “Drugs, Leads, and Drug-Likeness: An analysis of some recently launched drugs”, Proudfoot, DOI
Describes how most-drugs launched that year (2002) were very similar to the hits that spawned them, both in terms of molecular weight and LogP. With an added kick in the teeth for HTS.
3. “A Comparison of Physicochemical Property Profiles of Development and Marketed Oral Drugs”, Wenlock, JMC 2003 1250, DOI
Shows how attrition through the phases of clinical trials favours drug candidates with lower molecular weight and lower LogP.
4. “Utilization of Operational Schemes for Analog Synthesis in Drug Design”, Topliss, JMC 1972 1006, DOI
Your old-school med chem approach based on modulating the substituents on aromatic rings using a decision tree.
5. “Molecular Properties That Influence the Oral Bioavailability of Drug Candidates”, Veber, JMC 2002 2615, DOI
Describes what are often called Veber’s rules - specifically on PSA and rotatable bond count.
6. “Influence of Molecular Flexibility and Polar Surface Area Metrics on Oral Bioavailability in the Rat”, Burton, JMC 2004 6104, DOI
Pfizer’s take on Veber’s Rules, showing how different software calculates PSA and rotatable bond count differently, and should thus be used with caution.
7. “Features of Selective Kinase Inhibitors”, Shokat, DOI
Absolute must read for those working in kinase space. Good explanations of many things kinase related.
8. “Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors”, Liao, JMC 2007 409, DOI
This came in for a bit of stick when the ASAP appeared due to numerous errors. Most now corrected, and providing a good overview of kinase structural biology and features that can be exploited in ligand design.
9. “Structure-Brain Exposure Relationships”, Hitchcock, JMC 2006 7559, DOI
Good look into factors affecting how ligands should be designed/modified so as to cross or not cross the blood brain barrier as required. Good read.
10. “ADME/PK as part of a rational approach to drug discovery”, Eddershaw, DOI
Nice introduction to why early ADME/PK should pay off in discovery, outlining most of the things that med chemists should be looking to measure and optimise.
11. “Medicinal Chemistry of hERG Optimizations: Highlights and Hang-Ups”, Jamieson, JMC 2006 5029, DOI
Nice guide to hERG related issues, assays, and how to overcome hERG related problems
12. “Ligand efficiency indices as guideposts for drug discovery”, Abad-Zapatero, DOI
Maybe one for the fragment-based community - but illustrating why it’s easier in general to optimise an efficient ligand rather than an ugly, horrid inefficient one.
13. “Defining and maintaining a high quality screening collection: the GSK experience”, Lane, DOI
Describes things that can and do go wrong with HTS collections, and what to look out for and do about it
14. “A High-Throughput Screen for Aggregation-Based Inhibition in a Large Compound Library” Stoichet, JMC ASAP, DOI
Recent work from Stoichet on the tell-tale signs to look for when analysing HTS hits for those nasty promiscuous/aggregating inhibitors
15. “A Bioavailability Score”, Martin, JMC 2005 3164, DOI
Predicting oral availability in the rat. Into the realms of the Black Art, so a bit hit-and-miss, but suggests keeping PSA low.
16. “Dependence of Molecular Properties on Proteomic Family for Marketed Oral Drugs”, Vieth, JMC, 2006, 3541, DOI,
Variation on Lipinski’s rules, with a dash of Veber thrown in, looking at how these rules should be bent depending on target class
17. “The Identification of Toxicophores for the Prediction Mutagenicity, Hepatotoxicity and Cardiotoxicity”, Hakimelahi, click here
Structures of known toxicophores, and the mechanisms by which they operate.
18. “Derivation and Validation of Toxicophores for Mutagenicity Prediction”, Kazius et al, JMC, 2005, 312-320 (DOI)
Stuctures of known toxicophores from Organon
19. “Importance of Early Assessment of Bioactivation in Drug Discovery”, Hop et al, Annual Reports in Medicinal Chemistry, 2006, 369 (DOI)
Decent review from a Pfizer team on why this is important
20. “Predicting and Tuning Physicochemical Properties in Lead Optimization: Amine Basicity”, Morgenthaler et al, ChemMedChem, 2007, 1100 (DOI)
Everything you ever wanted to know about amine basicity, and how to modulate it.
21. “Fluorine in Pharmaceuticals: Looking Beyond Intuition”, Muller at al., Science, 2007, 1881-1886 (DOI)
22. “The Many Roles for Fluorine in Medicinal Chemistry”, Hagmann, J. Med. Chem, 2008 (DOI)
What fluorine can do for you.
23. “The significance of mitochondrial toxicity testing in drug development”, Dykens, Drug Discovery Today, 2007 (DOI)
24. “Preclinical in vitro screening assays for drug-like properties”, Li, Drug Discovery Today, 2005, (DOI)
