GRAM: A True Null Model for Relative Binding Affinity Predictions.

Relative binding affinity prediction is a critical component in computer aided drug design. A significant amount of effort has been dedicated to developing rapid and reliable methods. However, robust assessment of their performance is still a complicated issue, as it requires a performance measure applicable in the prospective setting and more importantly a true null model that defines the expected performance of being random in an objective manner.

Modeling the value of predictive affinity scoring in preclinical drug discovery.

Drug discovery is widely recognized to be a difficult and costly activity in large part due to the challenge of identifying chemical matter which simultaneously optimizes multiple properties, one of which is affinity for the primary biological target. Further, many of these properties are difficult to predict ahead of expensive and time-consuming compound synthesis and experimental testing. Here we highlight recent work to develop compound affinity prediction models, and extensively investigate the value such models may provide to preclinical drug discovery.

Chemoselective One-Pot Synthesis of Functionalized Amino-azaheterocycles Enabled by COware.

Functionalized bicyclic amino-azaheterocycles are rapidly accessed in a one-pot cross-coupling/reduction sequence enabled by the use of COware. Incompatible reagents are physically separated in a single reaction vessel to effect two chemoselective transformations-Suzuki-Miyaura cross-coupling and heteroarene reduction. The developed method allows access to novel heterocyclic templates, including semisaturated Hedgehog and dual PI3K/mTOR inhibitors, which show enhanced physicochemical properties compared to their unsaturated counterparts.

A Perspective on Water Site Prediction Methods for Structure Based Drug Design.

Over the last decade, a number of computational methods have been developed, which attempt to evaluate the thermodynamic properties of individual water molecules at the solute-solvent interface, in order to assess contributions to protein-ligand binding. In some cases, these tools tell us what we already know, e.g.

Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA Inhibitor.

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA inhibitors to act as bioisosteric phenyl replacements.

CADD medicine: design is the potion that can cure my disease.

The acronym "CADD" is often used interchangeably to refer to "Computer Aided Drug Discovery" and "Computer Aided Drug Design". While the former definition implies the use of a computer to impact one or more aspects of discovering a drug, in this paper we contend that computational chemists are most effective when they enable teams to apply true design principles as they strive to create medicines to treat human disease. We argue that teams must bring to bear multiple sub-disciplines of computational chemistry in an integrated manner in order to utilize these principles to address the multi-objective nature of the drug discovery problem.

Collaborating to improve the use of free-energy and other quantitative methods in drug discovery.

In May and August, 2016, several pharmaceutical companies convened to discuss and compare experiences with Free Energy Perturbation (FEP). This unusual synchronization of interest was prompted by Schrödinger's FEP+ implementation and offered the opportunity to share fresh studies with FEP and enable broader discussions on the topic. This article summarizes key conclusions of the meetings, including a path forward of actions for this group to aid the accelerated evaluation, application and development of free energy and related quantitative, structure-based design methods.

Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA).

Lp-PLA has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC > 1 mM).

Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening.

Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273).

SPAM: A Simple Approach for Profiling Bound Water Molecules.

A method that identifies the hydration shell structure of proteins and estimates the relative free energies of water molecules within that hydration shell is described. The method, which we call "SPAM" (maps spelled in reverse), utilizes explicit solvent molecular dynamics (MD) simulations to capture discrete hydration sites at the water-protein interface and computes a local free energy measure from the distribution of interaction energies between water and the environment at a specific site. SPAM is able to provide a qualitative estimate of the thermodynamic profile of bound water molecules that correlates nicely with well-studied structure-activity relationships and observed binding "hot spots".

Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors.

The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.

Discovery and initial optimization of 5,5'-disubstituted aminohydantoins as potent beta-secretase (BACE1) inhibitors.

8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.

Dual acting norepinephrine reuptake inhibitors and 5-HT(2A) receptor antagonists: Identification, synthesis and activity of novel 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles.

The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.

Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols.

A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC(50)=28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.

Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors.

Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified.

Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1 and S3 substrate binding pockets.

Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.

Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1' substrate binding pocket.

The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead.

Thiophene substituted acylguanidines as BACE1 inhibitors.

A series of thiophene-substituted acylguanidines were designed from a pyrrole substituted acylguanidine HTS lead. This template allowed a greater flexibility, through differential Suzuki couplings, to explore the binding site of BACE1 and to enhance the inhibitory potencies. This exploration provided a 25-fold enhancement in potency to yield compound 10a, which was 150 nM in a BACE1 FRET assay.

ERbeta ligands. Part 6: 6H-Chromeno[4,3-b]quinolines as a new series of estrogen receptor beta-selective ligands.

A new class of estrogen receptor beta (ERbeta) ligands based on the 6H-chromeno[4,3-b]quinoline scaffold has been prepared. Several C7-substituted analogues displayed high affinity and modest selectivity for ERbeta.

Hydrates and solid-state reactivity: a survey of beta-lactam antibiotics.

Crystalline hydrates of hydrolytically susceptible pharmaceuticals are commonly encountered, and are particularly prevalent in the beta-lactam class of antibiotics. In order to rationalize how the apparent chemical incompatibility between water and beta-lactams is reduced through crystallization, a review of the published literature and available structural information on the solid state stability was undertaken. A search in the CSD yielded a total of 32 crystal structures of water-containing beta-lactams which were examined and classified in terms of hydrogen-bonded networks.

ERbeta ligands. Part 5: synthesis and structure-activity relationships of a series of 4'-hydroxyphenyl-aryl-carbaldehyde oxime derivatives.

A series of 4'-hydroxyphenyl-aryl-carbaldehyde oximes (5b) was prepared and found to have high affinity (4nM) and modest selectivity (39-fold) for estrogen receptor-beta (ERbeta). Substitution of one of the core rings of the scaffold based around these novel ligands further expanded our knowledge in the quest toward achieving high affinity and selectivity for ERbeta. An X-ray co-crystal of structure 11 revealed that the oxime moiety was mimicking the C-ring of genistein, as previously predicted by SAR and docking studies.

Critical evaluation of methods to incorporate entropy loss upon binding in high-throughput docking.

Proper accounting of the positional/orientational/conformational entropy loss associated with protein-ligand binding is important to obtain reliable predictions of binding affinity. Herein, we critically examine two simplified statistical mechanics-based approaches, namely a constant penalty per rotor method, and a more rigorous method, referred to here as the partition function-based scoring (PFS) method, to account for such entropy losses in high-throughput docking calculations. Our results on the estrogen receptor beta and dihydrofolate reductase proteins demonstrate that, while the constant penalty method over-penalizes molecules for their conformational flexibility, the PFS method behaves in a more "DeltaG-like" manner by penalizing different rotors differently depending on their residual entropy in the bound state.

Acylguanidines as small-molecule beta-secretase inhibitors.

BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation.

ERbeta ligands. Part 4: Synthesis and structure-activity relationships of a series of 2-phenylquinoline derivatives.

A new class of estrogen receptor beta (ERbeta) ligands based on the 2-phenylquinoline scaffold was prepared. Several analogues with C4 substitution displayed high affinity (3-5 nM) and significant selectivity (up to 83-fold) for ERbeta. The best compound, 13b, was profiled as a selective partial agonist for ERbeta at 1 muM in a cell-based transcriptional assay.

ERbeta ligands. 3. Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERbeta selectivity.

The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein.