A. Peter Johnson

SPROUT: a program for structure generation.

SummarySPROUT is a new computer program for constrained structure generation that is designed to generate molecules for a range of applications in molecular recognition. It uses artificial intelligence techniques to moderate the combinatorial explosion that is inherent in structure generation. The program is presented here for the design of enzyme inhibitors. Structure generation is divided into two phases: (i) primary structure generation to produce molecular graphs to fit the steric constraints; and (ii) secondary structure generation which is the process of introducing appropriate functionality to the graphs to produce molecules that satisfy the secondary constraints, e.g., electrostatics and hydrophobicity. Primary structure generation has been tested on two enzyme receptor sites; the p-amidino-phenyl-pyruvate binding site of trypsin and the acetyl pepstatin binding site of HIV-1 protease. The program successfully generates structures that resemble known substrates and, more importantly, the predictive power of the program has been demonstrated by its ability to suggest novel structures.

SPROUT, HIPPO and CAESA: Tools for de novo structure generation and estimation of synthetic accessibility

Several components of a system for structure generation are now well developed. HIPPO is a program that characterises a receptor binding site for potential target sites within the cavity that can be used in de novo design. The target sites include simple and complex hydrogen bonds, covalent bonds and bonds to metal ions. The SPROUT program for structure generation consists of two main components: the first is skeleton generation, followed by atom substitution to convert the solution skeletons to molecules. A new method of skeleton generation is presented here, where part skeletons are grown outwards from each target site. The part skeletons are then connected together to form solution skeletons. Finally the CAESA program is described, that ranks the output from SPROUT according to ease of synthesis.

Route Designer: A Retrosynthetic Analysis Tool Utilizing Automated Retrosynthetic Rule Generation

Route Designer, version 1.0, is a new retrosynthetic analysis package that generates complete synthetic routes for target molecules starting from readily available starting materials. Rules describing retrosynthetic transformations are automatically generated from reaction databases, which ensure that the rules can be easily updated to reflect the latest reaction literature. These rules are used to carry out an exhaustive retrosynthetic analysis of the target molecule, in which heuristics are used to mitigate the combinatorial explosion. Proposed routes are prioritized by an empirical rating algorithm to present a diverse profile of the most promising solutions. The program runs on a server with a web-based user interface. An overview of the system is presented together with examples that illustrate Route Designers utility.

The CIP sequence rules: Analysis and proposal for a revision

Abstract In spite of their value and wide usage the Cahn, Ingold and Prelog (CIP) Sequence Rules have some deficiencies. In particular incompleteness, inconsistency and ambiguity can arise in their application to complex molecules. Therefore, a complete analysis of the CIP Sequence Rules has been made and modified rules are proposed.

Molecular mechanism of ligand recognition by membrane transport protein, Mhp1

The hydantoin transporter Mhp1 is a sodium‐coupled secondary active transport protein of the nucleobase‐cation‐symport family and a member of the widespread 5‐helix inverted repeat superfamily of transporters. The structure of Mhp1 was previously solved in three different conformations providing insight into the molecular basis of the alternating access mechanism. Here, we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site‐directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands. We show precisely where 5‐substituted hydantoin substrates bind in an extended configuration at the interface of the bundle and hash domains. They are recognised through hydrogen bonds to the hydantoin moiety and the complementarity of the 5‐substituent for a hydrophobic pocket in the protein. Furthermore, we describe a novel structure of an intermediate state of the protein with the external thin gate locked open by an inhibitor, 5‐(2‐naphthylmethyl)‐L‐hydantoin, which becomes a substrate when leucine 363 is changed to an alanine. We deduce the molecular events that underlie acquisition and transport of a ligand by Mhp1.

Macrocyclic inhibitors of the bacterial cell wall biosynthesis enzyme mur D

Computer-based molecular design has been used to produce a series of new macrocyclic systems targeted against the bacterial cell wall biosynthetic enzyme MurD. Following their preparation, which involved a novel metathesis-based cyclisation as the key step, these systems were found to show good inhibition when assayed against the MurD enzyme.

Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness.

cAMP mediates autonomic regulation of heart rate by means of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder β-adrenergic stimulation on If. Our results highlight the regulative role of the C-linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system.

Computer-aided synthesis design: 40 years on

The discipline of retrosynthetic analysis is now just over 40 years old. From the earliest day, attempts were made to incorporate this approach into computer programs to test the extent in which chemical perception and synthetic thinking could be formalized. Despite pioneering research efforts, computer‐aided synthetic analysis failed to achieve widespread routine use by chemists, which can be attributed in part to the difficulty of building the required high‐quality retrosynthetic transform databases required for credible analyses. However, with the advent over the past 25 years of large comprehensive reaction databases, work on successfully automating the construction of reliable and comprehensive reaction rule databases is promising to revitalize research in this field. This review compares and contrasts the diverse approaches taken by selected programs in both the design and implementation of molecule feature perception and reaction rule representation, and we review the concepts of synthetic strategy selection, representation, and execution. In particular, we discuss the current work on automating the construction of reliable and comprehensive synthetic rule sets from available reaction databases in newer programs such as ARChem. We argue that the progress achieved in this aspect paves the way to a deeper exploration of computer approaches to applying strategy and control in the synthesis problem.

An artificial neural network for classifying cross peaks in two-dimensional NMR spectra

Abstract A simulated neural network is described that has been trained to classify cross peaks in the 2D NMR spectra of biological macromolecules. The trained network has then been used to classify previously unseen data. The network is able to distinguish between authentic cross peaks and spectral artifacts, such as those arising from presaturation of water, noise, and t1 noise. Moreover, the network is able to recognize genuine peaks whose shapes have been modified, for example, by overlap with other real or spurious peaks. Herein, the training and performance of the network are demonstrated for a NOESY spectrum.

Synthesis of hindered spiro-oxindoles by photolysis of 1-(1-alkenyl)benzotriazoles

Abstract Photolysis of 1-(1-alkoxy-1-alkenyl)benzotriazoles gives moderate yields of 2-alkoxy-indolenines, which can be hydrolysed to oxindoles. A side reaction leads to the formation of imino-oxetanes. The formation of the 2-alkoxy-indolenines is quite insensitive to steric hindrance at the reacting centres.