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Although it is extremely challenging to invent new medicines, I have observed that certain behaviors seem to be commonly found among successful medicinal chemists. Those who exhibit most of these character traits are far more likely to bring new drugs into the clinic and onto the market. And, importantly, organizations that encourage these behaviors are far more likely to be successful. These traits can be broken into two categories: “general” and “discipline-specific”. General traits are those that are common to all great scientists, while the discipline-specific ones are more specialized behaviors relevant to the medicinal chemistry enterprise. I describe these traits, and include some specific examples for each of the medicinal chemistry characteristics that I hope will be illustrative. While success in drug discovery is never guaranteed, I believe that embracing and encouraging these behaviors increase the probability of a successful outcome.

© 2015 American Chemical Society. Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.

Despite massive advances in basic knowledge, technology, and availability of medical and biological data during the past few decades, transformational breakthroughs in medicine have yet to be seen, and yet, a bright future where medicine is can be imagined, in Leroy Hood's memorable formulation, “personalized, predictive, preventative, and participatory.” How will we get to that bright future? As a thought experiment, how a drug for rheumatoid arthritis may be discovered 25 years from now can be imagined in detail, and the additional breakthroughs in technology and processes that will occur in the subsequent decade leading to the mid-century mark can be further speculated. Of course all such predictions are inevitably wrong; but the aim of such prognostication is to stimulate fresh thinking about what must happen for that desired future state to come into existence. Accordingly, the specific and significant changes that must occur across every aspect of the process, ranging from the technologies ...

Powerful technologies allow the synthesis and testing of large numbers of new compounds, but the failure rate of pharmaceutical R&D remains very high. Greater understanding of the fundamental physical chemical behaviour of molecules could be the key to greatly enhancing the success rate of drug discovery.

Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. We investigated the phenomenon of kinase-likeness, i.e., the propensity of ligands to inhibit protein kinases, in the context of kinase-specific substructural fragments. The frequency of occurrence of multiple structural fragments in kinase inhibitor libraries relative to nonkinase compounds has been analyzed. A combination of structural fragment counts, termed the "2-0" kinase-likeness rule, provides approximately 5-fold enrichment in kinase active compounds. This rule has been validated using in-house kinase counterscreening data and applied prospectively to uncover kinase activities in marketed drugs. In addition, the role of discriminating fragments in kinase recognition was interrogated using available structural data, providing an insight into their effect on inhibitor potency and selectivity. One of these fragments, bisarylaniline, has been characterized as a kinase-privileged fragment with specific binding preferences and a link to increased activity within kinases.

Reversible tetrapeptide-based compounds have been shown to effectively inhibit the hepatitis C virus NS3.4A protease. Inhibition of viral replicon RNA production in Huh-7 cells has also been demonstrated. We show herein that the inclusion of hydrogen bond donors on the P4 capping group of tetrapeptide-based inhibitors result in increased binding potency to the NS3.4A protease. The capping groups also impart significant effects on the pharmacokinetic profile of these inhibitors.

We recently described the identification of an optimized α-ketoamide warhead for our series of HCV NS3·4A inhibitors. We report herein a series of HCV protease inhibitors incorporating 3-alkyl-substituted prolines in P2. These compounds show exceptional enzymatic and cellular potency given their relatively small size. The marked enhancement of activity of these 3-substituted proline derivatives relative to previously reported 4-hydroxyproline derivatives constitutes additional evidence for the importance of the S2 binding pocket as the defining pharmacophore for inhibition of the NS3·4A enzyme.

VX-787 is a novel inhibitor of influenza virus replication that blocks the PB2 cap-snatching activity of the influenza viral polymerase complex. Viral genetics and X-ray crystallography studies provide support for the idea that VX-787 occupies the 7-methyl GTP (m 7 GTP) cap-binding site of PB2. VX-787 binds the cap-binding domain of the PB2 subunit with a K D (dissociation constant) of 24 nM as determined by isothermal titration calorimetry (ITC). The cell-based EC 50 (the concentration of compound that ensures 50% cell viability of an uninfected control) for VX-787 is 1.6 nM in a cytopathic effect (CPE) assay, with a similar EC 50 in a viral RNA replication assay. VX-787 is active against a diverse panel of influenza A virus strains, including H1N1pdm09 and H5N1 strains, as well as strains with reduced susceptibility to neuraminidase inhibitors (NAIs). VX-787 was highly efficacious in both prophylaxis and treatment models of mouse influenza and was superior to the neuraminidase inhibitor, oseltamivir, including in delayed-start-to-treat experiments, with 100% survival at up to 96 h postinfection and partial survival in groups where the initiation of therapy was delayed up to 120 h postinfection. At different doses, VX-787 showed a 1-log to >5-log reduction in viral load (relative to vehicle controls) in mouse lungs. Overall, these favorable findings validate the PB2 subunit of the viral polymerase as a drug target for influenza therapy and support the continued development of VX-787 as a novel antiviral agent for the treatment of influenza infection.

In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.

Library design is an important and difficult task. In this paper we describe one possible solution to designing a CNS-active library. CNS-actives and -inactives were selected from the CMC and the MDDR databases based on whether they were described as having some kind of CNS activity in the databases. This classification scheme results in over 15 000 actives and over 50 000 inactives. Each molecule is described by 7 1D descriptors (molecular weight, number of donors, number of acceptors, etc.) and 166 2D descriptors (presence/absence of functional groups such as NH(2)). A neural network trained using Bayesian methods can correctly predict about 75% of the actives and 65% of the inactives using the 7 1D descriptors. The performance improves to a prediction accuracy on the active set of 83% and 79% on the inactives on adding the 2D descriptors. On a database with 275 compounds where the CNS activity is known (from the literature) for each compound, we achieve 92% and 71% accuracy on the actives and inactives, respectively. The models we construct can therefore be used as a "filter" to examine any set of proposed molecules in a chemical library. As an example of the utility of our method, we describe the generation of a small library of potentially CNS-active molecules that would be amenable to combinatorial chemistry. This was done by building and analyzing a large database of a million compounds constructed from frameworks and side chains frequently found in drug molecules.

Background: Recently, it has been shown that nuclear magnetic resonance (NMR) may be used to identify ligands that bind to low molecular weight protein drug targets. Recognizing the utility of NMR as a very sensitive method for detecting binding, we have focused on developing alternative approaches that are applicable to larger molecular weight drug targets and do not require isotopic labeling. Results: A new method for lead generation (SHAPES) is described that uses NMR to detect binding of a limited but diverse library of small molecules to a potential drug target. The compound scaffolds are derived from shapes most commonly found in known therapeutic agents. NMR detection of low (μM-mM) affinity binding is achieved using either differential line broadening or transferred NOE (nuclear Overhauser effect) NMR techniques. Conclusions: The SHAPES method for lead generation by NMR is useful for identifying potential lead classes of drugs early in a drug design program, and is easily integrated with other discovery tools such as virtual screening, high-throughput screening and combinatorial chemistry.

A variety of successful approaches to the problem of recognizing 'drug-like' molecules have been employed. These range from simple counting schemes such as the Lipinski 'rule of five' to the analysis of the multidimensional 'chemistry space' occupied by drugs, to neural network learning systems. With this variety of tools, it now appears possible to design libraries that are enriched in compounds which have desirable or 'drug-like' properties. Verifying the robustness of these methods, and extending them, will form the basis of research in this field during the next few years.

Thrombin plays a central role in thrombosis. Because of the medical need for novel antithrombotic drugs, a search for structurally novel thrombin inhibitors was undertaken. In the absence of a crystal structure, a class was designed based on a modeling approach which involved placing the essential functional groups of the thrombin antagonist MD-805 [1] (Argatroban) into the benzodiazepine nucleus. The best superposition was obtained with a 1,4-benzodiazepin-2-one containing a 1,2,3,4-tetrahydro quinolylsulfonyl moiety in the 3-position, a guanidino-phenyl at the 5-position, and N 1 -substituted with an acetic acid. Synthesis of these molecules provided compounds with an inhibitory activity with K 1 in the range of 40–1000 μJ.M. A report on the crystal structure of thrombin * hirudin(55-65) * MD-805 complex [2] suggested subsequent molecular modeling investigations to rationalize the pharmacological results.

Recent advances in combinatorial chemistry and high-throughput screening have made it possible for chemists to synthesize large numbers of compounds. However, this is still a small percentage of the total number that could be synthesized. Virtual screening encompasses a variety of computational techniques that allow chemists to reduce a huge virtual library to a more manageable size. This review presents the current state of the art in virtual screening and discusses approaches that will allow the evaluation of larger numbers of compounds.

Background: Hepatitis C virus (HCV) represents a major health concern as it is responsible for a significant number of hepatitis cases worldwide. Much research has focused on the replicative enzymes of HCV as possible targets for more effective therapeutic agents. HCV NS3 helicase may provide one such suitable target. Helicases are enzymes which can unwind double-stranded regions of DNA or RNA in an ATP-dependent reaction. The structures of several helicases have been published but the structural details as to how ATP binding and hydrolysis are coupled to DNA unwinding are unknown. Results: The structure of the HCV NS3 RNA helicase domain complexed with a single-stranded DNA oligonucleotide has been solved to 2.2 a resolution. The protein consists of three structural domains with the oligonucleotide lying in a groove between the first two domains and the third. The first two domains have an adenylate kinase like fold, including a phosphate-binding loop in the first domain. Conclusions: HCV NS3 helicase is a member of a superfamily of helicases, termed superfamily II. Residues of NS3 helicase which are conserved among superfamily II helicases line an interdomain cleft between the first two domains. The oligonucleotide binds in an orthogonal binding site and contacts relatively few conserved residues. There are no strong sequence-specific interactions with the oligonucleotide bases.

The large effects on the singlet–triplet energy difference, ΔEST, of substituting oxygen atoms for one or two methylene groups in trimethylenemethane and in 2,4-dimethylenecyclobutane-1,3-diyl are discussed. In contrast, CASSCF and CASPT2N/6-31G* calculations predict only small changes in ΔEST on substituting oxygen atoms for one or two methylene groups in m-benzoquinodimethane. After corrections for differences in zero-point energies and heat capacities, CASPT2N/6-31G* calculations give ΔEST = 11.0 kcal mol–1 for m-benzoquinodimethane, which is very close to the experimental value of ΔEST = 9.6 ± 0.2 kcal mol–1. At the same level of theory ΔEST = 9.3 and 11.8 kcal mol–1 are computed for, respectively, m-benzoquinomethane and m-benzoquinone. The reasons why substitution of oxygen atoms for one or two methylene groups is predicted to have such a small effect on ΔEST in these three diradicals is discussed. As expected, for 1,3-naphthoquinomethane CASPT2N predicts a value of ΔEST that is only slightly larger than that in m-benzoquinomethane. However, the calculated value of ΔEST = 11.6 kcal mol–1 is 7 kcal mol–1 lower than the value measured by photoacoustic calorimetry.

By use of geometric/conformational constraints and extensions, it is possible to test the limits to which intramolecular exchange may be controlled in conjugated, open-shell organic models for large, extended polyradicals and magnetic domains.

Pyridone derivatives, especially with 6-aryl substituents, have been shown to be useful P2-P3 peptidomimetic scaffolds for the design of potent inhibitors of ICE.

The very potent HIV-1 protease (HIV-PR) inhibitor, KNI-272, contains a norstatine–thioproline linkage at P1–P1′. The three-dimensional crystal structure of this compound bound to HIV-PR has recently been determined [Baldwin et al., Structure, 3, 581 (1995)]. The crystal structure reveals a number of interesting interactions previously unseen in bound HIV-PR inhibitors. Here, we employ high-level ab initio calculations and molecular modeling to ascertain the strain energy of the bound conformation of the norstatine–thioproline portion of KNI-272. Baldwin et al. suggested that two of the reasons for the high potency of KNI-272 are the rigidity of its backbone and a strong preference for the norstatine–thioproline amide linkage to adopt a trans conformation. Our analysis shows that, on the contrary, there is still considerable flexibility in the backbone of the norstatine-based inhibitor. Furthermore, in the gas phase and in solution, there are both cis and trans conformations of the norstatine–thioproline amide linkage which are low in energy. However, when bound in the active site of HIV-PR, KNI-272 clearly has a strong preference for a trans conformation, which enables the formation of hydrogen bonds to the flap water. Our calculations, at level up to MP2/6-31++G//HF/6-31G*, suggest that the bound, trans amide conformation of the norstatine–thioproline “core” is still strained by 2–3 kcal/mol, primarily due to the placement of the P1′ thioproline carboxamide. This result is consistent with those previously obtained for the related protease inhibitor Ro 31-8959 (Saquinovir), which also requires a carboxamide to adopt a high-energy rotamer to preserve a good hydrogen bond to the flap water. However, the strain of the bound conformation of KNI-272 is clearly lower than that of Saquinovir. In addition, because the norstatine linkage does not contain a basic amine (as do Saquinovir and JG-365, for example) it should be easier to desolvate, which also assists in binding. The relationship between KNI-272, JG-365, Saquinovir, and P1′ proline-containing substrate also is discussed. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1151–1166

Members of the Flaviviridae encode a serine proteinase termed NS3 that is responsible for processing at several sites in the viral polyproteins. In this report, we show that the NS3 proteinase of the pestivirus bovine viral diarrhea virus (BVDV) (NADL strain) is required for processing at nonstructural (NS) protein sites 3/4A, 4A/4B, 4B/5A, and 5A/5B but not for cleavage at the junction between NS2 and NS3. Cleavage sites of the proteinase were determined by amino-terminal sequence analysis of the NS4A, NS4B, NS5A, and NS5B proteins. A conserved leucine residue is found at the P1 position of all four cleavage sites, followed by either serine (3/4A, 4B/5A, and 5A/5B sites) or alanine (4A/4B site) at the P1' position. Consistent with this cleavage site preference, a structural model of the pestivirus NS3 proteinase predicts a highly hydrophobic P1 specificity pocket. trans-Processing experiments implicate the 64-residue NS4A protein as an NS3 proteinase cofactor required for cleavage at the 4B/5A and 5A/5B sites. Finally, using a full-length functional BVDV cDNA clone, we demonstrate that a catalytically active NS3 serine proteinase is essential for pestivirus replication.

Free energy simulations have been employed to rationalize the binding differences between A-74704, a pseudo C2-symmetric inhibitor of HIV-1 protease and its diester analog. The diester analog inhibitor, which misses two hydrogen bonds with the enzyme active site, is surprisingly only 10-fold weaker. The calculated free energy difference of 1.7 +/- 0.6 kcal/mol is in agreement with the experimental result. Further, the simulations show that such a small difference in binding free energies is due to (1) weaker hydrogen bond interactions between the two (P1 and P1') NH groups of A-74704 with Gly27/Gly27' carbonyls of the enzyme and (2) the higher desolvation free energy of A-74704 compared with its ester analog. The results of these calculations and their implications for design of HIV-1 protease inhibitors are discussed.

In order to better understand the common features present in drug molecules, we use shape description methods to analyze a database of commercially available drugs and prepare a list of common drug shapes. A useful way of organizing this structural data is to group the atoms of each drug molecule into ring, linker, framework, and side chain atoms. On the basis of the two-dimensional molecular structures (without regard to atom type, hybridization, and bond order), there are 1179 different frameworks among the 5120 compounds analyzed. However, the shapes of half of the drugs in the database are described by the 32 most frequently occurring frameworks. This suggests that the diversity of shapes in the set of known drugs is extremely low. In our second method of analysis, in which atom type, hybridization, and bond order are considered, more diversity is seen; there are 2506 different frameworks among the 5120 compounds in the database, and the most frequently occurring 42 frameworks account for only one-fourth of the drugs. We discuss the possible interpretations of these findings and the way they may be used to guide future drug discovery research.

We have implemented and tested a new approach to de novo ligand design, CONCERTS (creation of novel compounds by evaluation of residues at target sites). In this method, each member of a user-defined set of fragments is allowed to move independently about a target active site during a molecular dynamics simulation. This allows the fragments to sample various low-energy orientations. When the geometry between proximal fragments is appropriate, bonds can be formed between the fragments. In this fashion, larger molecules can be built. The bonding arrangement can subsequently be changed-breaking bonds between chosen fragment pairs and forming them between other pairs-if the overall process creates lower energy molecules. We have tested this method with various mixes of fragments against the active sites of the FK506 binding protein (FKBP-12) and HIV-1 aspartyl protease. In several cases, CONCERTS suggests ligands which are in surprisingly good agreement with known inhibitors of these proteins.

FK506 (tacrolimus) is a natural product now approved in the US and Japan for organ transplantation. FK506, in complex with its 12 kDa cytosolic receptor (FKBP12), is a potent agonist of immunosuppression through the inhibition of the phosphatase activity of calcineurin. Rapamycin (sirolimus), which is itself an immunosuppressant by a different mechanism, completes with FK506 for binding to FKBP12 and thereby acts as an antagonist of calcineurin inhibition. We have solved the X-ray structure of unliganded FKBP12 and of FKBP12 in complex with FK506 and with rapamycin; these structures show localized differences in conformation and mobility in those regions of the protein that are known, by site-directed mutagenesis, to be involved in calcineurin inhibition. A comparison of 16 additional X-ray structures of FKBP12 in complex with FKBP12-binding ligands, where those structures were determined from different crystal forms with distinct packing arrangements, lends significance to the observed structural variability and suggests that it represents an intrinsic functional characteristic of the protein. Similar differences have been observed for FKBP12 before, but were considered artifacts of crystal-packing interactions. We suggest that immunosuppressive ligands express their differential effects in part by modulating the conformation of FKBP12, in agreement with mutagenesis experiments on the protein, and not simply through differences in the ligand structures themselves.

The tetrapeptide aldehyde Ac-Tyr-Val-Ala-AspH ( 1 , L-709,049) has been reported to be a potent reversible inhibitor of Interleukin-1β Converting Enzyme (ICE). We have prepared a series of analogs of 1 , in order to explore the active sige of ICE. The effects of truncation, methylation of the amide nitrogens and modification of the aldehyde group of 1 are presented.

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38α inhibitors is described. Application of structural information from enzyme–ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38α inhibitors containing a previously unreported bicyclic heterocycle core. Advancing the SAR of this series led to the eventual discovery of 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one (VX-745). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.