Symmetric Kv1.5 Blockers Discovered by Focused Screening

Guided by computational methods, a set of 1920 compounds were selected from the AstraZeneca corporate collection and screened for Kv1.5 activity. To facilitate rapid generation of structure–activity relationships, special attention was given to selecting subsets of structurally similar molecules by using a maximum common substructure similarity-based procedure. The focused screen hit rate was relatively high (12%). More importantly, a structural series featured by the symmetric 1,2-diphenylethane-1,2-diamine substructure was identified as potent Kv.1.5 blockers. The property profile for the series is shown to meet stringent lead-optimization criteria, providing a springboard for the development of a new and safe treatment for atrial fibrillation

Where Do Recent Small Molecule Clinical Development Candidates Come From?

An analysis of 66 published clinical candidates from <i>Journal of Medicinal Chemistry</i> has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = −0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed

Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki–Miyaura and Buchwald–Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki–Miyaura coupling, and S_NAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design

ReFlex3D: Refined Flexible Alignment of Molecules Using Shape and Electrostatics

We present an algorithm, ReFlex3D, for the refinement of flexible molecular alignments based on their three-dimensional shape and electrostatic properties. The algorithm is designed to be used with fast conformer generators to refine an initial overlay between two molecules and thus to obtain improved overlaps as judged by an increase in calculated similarity values. ReFlex3D is open-source and built as a python package working in combination with the OEChem Toolkit. As such it can readily be implemented in existing workflows ranging from the selection of compounds from a virtual screening campaign to the construction of similarity based prediction models to estimate binding affinities. We evaluate ReFlex3D against the AstraZeneca Validation Test Set and illustrate its potential within a predictive model compared to an established method (Posit)

An approximate approach to sample size determination in bioequivalence testing with multiple pharmacokinetic responses

[[abstract]]The approval of generic drugs requires the evidence of average bioequivalence (ABE) on both the area under the concentration–time curve and the peak concentration Cmax. The bioequivalence (BE) hypothesis can be decomposed into the non-inferiority (NI) and non-superiority (NS) hypothesis. Most of regulatory agencies employ the two one-sided tests (TOST) procedure to test ABE between two formulations. As it is based on the intersection–union principle, the TOST procedure is conservative in terms of the type I error rate. However, the type II error rate is the sum of the type II error rates with respect to each null hypothesis of NI and NS hypotheses. When the difference in population means between two treatments is not 0, no close-form solution for the sample size for the BE hypothesis is available. Current methods provide the sample sizes with either insufficient power or unnecessarily excessive power. We suggest an approximate method for sample size determination, which can also provide the type II rate for each of NI and NS hypotheses. In addition, the proposed method is flexible to allow extension from one pharmacokinetic (PK) response to determination of the sample size required for multiple PK responses. We report the results of a numerical study. An R code is provided to calculate the sample size for BE testing based on the proposed methods

ReFlex3D: Refined Flexible Alignment of Molecules Using Shape and Electrostatics

We present an algorithm, ReFlex3D, for the refinement of flexible molecular alignments based on their three-dimensional shape and electrostatic properties. The algorithm is designed to be used with fast conformer generators to refine an initial overlay between two molecules and thus to obtain improved overlaps as judged by an increase in calculated similarity values. ReFlex3D is open-source and built as a python package working in combination with the OEChem Toolkit. As such it can readily be implemented in existing workflows ranging from the selection of compounds from a virtual screening campaign to the construction of similarity based prediction models to estimate binding affinities. We evaluate ReFlex3D against the AstraZeneca Validation Test Set and illustrate its potential within a predictive model compared to an established method (Posit)

Understanding Our Love Affair with <i>p</i>‑Chlorophenyl: Present Day Implications from Historical Biases of Reagent Selection

We report here an unexpectedly strong preference toward para substitution in phenyl rings within drug discovery programs. A population analysis of aromatic rings in various drug databases demonstrated that para substitution is favored over meta and ortho regioisomers, with <i>p</i>-chlorophenyl (<i>p</i>-ClPh) being one of the most predominant examples. We speculate that the frequency of <i>p</i>-ClPh is traced back to historical models of medicinal chemistry where para-substituted regioisomers were perhaps more easily accessed, and further reinforced by Topliss in 1972 that if Ph was active, the <i>p</i>-ClPh should be made because of ease of synthesis and hydrophobicity driven potency effects. On the basis of our analysis, the para bias has become useful conventional wisdom but perhaps so much so that a perception has been created that druglike space favors a linear aromatic structure. It is hoped this analysis will catalyze a new look at design of reagent databases and screening collections

ReFlex3D: Refined Flexible Alignment of Molecules Using Shape and Electrostatics

We present an algorithm, ReFlex3D, for the refinement of flexible molecular alignments based on their three-dimensional shape and electrostatic properties. The algorithm is designed to be used with fast conformer generators to refine an initial overlay between two molecules and thus to obtain improved overlaps as judged by an increase in calculated similarity values. ReFlex3D is open-source and built as a python package working in combination with the OEChem Toolkit. As such it can readily be implemented in existing workflows ranging from the selection of compounds from a virtual screening campaign to the construction of similarity based prediction models to estimate binding affinities. We evaluate ReFlex3D against the AstraZeneca Validation Test Set and illustrate its potential within a predictive model compared to an established method (Posit)

ReFlex3D: Refined Flexible Alignment of Molecules Using Shape and Electrostatics

We present an algorithm, ReFlex3D, for the refinement of flexible molecular alignments based on their three-dimensional shape and electrostatic properties. The algorithm is designed to be used with fast conformer generators to refine an initial overlay between two molecules and thus to obtain improved overlaps as judged by an increase in calculated similarity values. ReFlex3D is open-source and built as a python package working in combination with the OEChem Toolkit. As such it can readily be implemented in existing workflows ranging from the selection of compounds from a virtual screening campaign to the construction of similarity based prediction models to estimate binding affinities. We evaluate ReFlex3D against the AstraZeneca Validation Test Set and illustrate its potential within a predictive model compared to an established method (Posit)

ReFlex3D: Refined Flexible Alignment of Molecules Using Shape and Electrostatics

We present an algorithm, ReFlex3D, for the refinement of flexible molecular alignments based on their three-dimensional shape and electrostatic properties. The algorithm is designed to be used with fast conformer generators to refine an initial overlay between two molecules and thus to obtain improved overlaps as judged by an increase in calculated similarity values. ReFlex3D is open-source and built as a python package working in combination with the OEChem Toolkit. As such it can readily be implemented in existing workflows ranging from the selection of compounds from a virtual screening campaign to the construction of similarity based prediction models to estimate binding affinities. We evaluate ReFlex3D against the AstraZeneca Validation Test Set and illustrate its potential within a predictive model compared to an established method (Posit)