SIME: synthetic insight-based macrolide enumerator to generate the V1B library of 1 billion macrolides

We report on a new cheminformatics enumeration technology—SIME, synthetic insight-based macrolide enumerator—a new and improved software technology. SIME can enumerate fully assembled macrolides with synthetic feasibility by utilizing the constitutional and structural knowledge extracted from biosynthetic aspects of macrolides. Taken into account by the software are key information such as positions in macrolide structures at which chemical components can be inserted, and the types of structural motifs and sugars of interest that can be synthesized and incorporated at those positions. Additionally, we report on the chemical distribution analysis of the newly SIME-generated V1B (virtual 1 billion) library of macrolides. Those compounds were built based on the core of the Erythromycin structure, 13 structural motifs and a library of sugars derived from eighteen bioactive macrolides. This new enumeration technology can be coupled with cheminformatics approaches such as QSAR modeling and molecular docking to aid in drug discovery for rational designing of next generation macrolide therapeutics with desirable pharmacokinetic properties.

[1]  Poul Nissen,et al.  The structures of four macrolide antibiotics bound to the large ribosomal subunit. , 2002, Molecular cell.

[2]  Matthew P Jacobson,et al.  Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. , 2006, Journal of the American Chemical Society.

[3]  Nancy A Milanesio,et al.  Cethromycin versus Clarithromycin for Community-Acquired Pneumonia: Comparative Efficacy and Safety Outcomes from Two Double-Blinded, Randomized, Parallel-Group, Multicenter, Multinational Noninferiority Studies , 2012, Antimicrobial Agents and Chemotherapy.

[4]  G. Amsden,et al.  Macrolide Drug Interactions: An Update , 2000, The Annals of pharmacotherapy.

[5]  Daniel J. Sindhikara,et al.  Improving Accuracy, Diversity, and Speed with Prime Macrocycle Conformational Sampling , 2017, J. Chem. Inf. Model..

[6]  D. Bertrand,et al.  The solithromycin journey-It is all in the chemistry. , 2016, Bioorganic & medicinal chemistry.

[7]  G. Dinos.  The macrolide antibiotic renaissance , 2017, British journal of pharmacology.

[8]  Dubravko Jelić,et al.  From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials , 2016, Antibiotics.

[9]  Joshua A. Kritzer,et al.  Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design , 2014, Nature chemical biology.

[10]  P. Raboisson.  Macrocycles: Under-Explored and Poorly Exploited Drug Class Despite the Proven Therapeutic Potential , 2015 .

[11]  Sean Ekins,et al.  Cheminformatics Analysis and Modeling with MacrolactoneDB , 2020, Scientific Reports.

[12]  C. Khosla,et al.  Combinatorial biosynthesis of polyketides--a perspective. , 2012, Current Opinion in Chemical Biology.

[13]  Fabrizio Giordanetto,et al.  Macrocyclic drugs and clinical candidates: what can medicinal chemists learn from their properties? , 2014, Journal of medicinal chemistry.

[14]  Hilde van der Togt,et al.  Publisher's Note , 2003, J. Netw. Comput. Appl..

[15]  P. Turner,et al.  Pharmacokinetic interaction between theophylline and erythromycin. , 1982, British journal of clinical pharmacology.

[16]  A. Yudin,et al.  Conformational Control of Macrocycles by Remote Structural Modification. , 2019, Chemical reviews.

[17]  Xavier Barbeau,et al.  ConfBuster: Open-Source Tools for Macrocycle Conformational Search and Analysis , 2018 .

[18]  R. Leclercq,et al.  Resistance to Macrolides and Related Antibiotics in Streptococcus pneumoniae , 2002, Antimicrobial Agents and Chemotherapy.

[19]  Andrew A. White,et al.  Macrolide antibiotics as anti-inflammatory agents , 2005, Current allergy and asthma reports.

[20]  Stephen R. Johnson,et al.  Molecular properties that influence the oral bioavailability of drug candidates. , 2002, Journal of medicinal chemistry.

[21]  Csaba Hetényi,et al.  Contribution of 2D and 3D Structural Features of Drug Molecules in the Prediction of Drug Profile Matching , 2012, J. Chem. Inf. Model..

[22]  Dima Kozakov,et al.  How Proteins Bind Macrocycles , 2014, Nature chemical biology.

[23]  M. Glaser,et al.  Predicting the bioactive conformations of macrocycles: a molecular dynamics-based docking procedure with DynaDock , 2019, Journal of Molecular Modeling.

[24]  Gavin Williams,et al.  Cheminformatics-based enumeration and analysis of large libraries of macrolide scaffolds , 2018, Journal of Cheminformatics.

[25]  Christopher A Lipinski,et al.  Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions. , 2016, Advanced drug delivery reviews.

[26]  E. Mini,et al.  Chemistry and mode of action of macrolides. , 1993, The Journal of antimicrobial chemotherapy.

[27]  J. Zuckerman,et al.  Macrolides, ketolides, and glycylcyclines: azithromycin, clarithromycin, telithromycin, tigecycline. , 2009, Infectious disease clinics of North America.

[28]  B. Rubin,et al.  Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications , 2010, Clinical Microbiology Reviews.

[29]  A. Pyka,et al.  A comparison of theoretical methods of calculation of partition coefficients for selected drugs. , 2006, Acta poloniae pharmaceutica.

[30]  Yasuaki Yamada,et al.  Azithromycin, clarithromycin and telithromycin inhibit MUC5AC induction by Chlamydophila pneumoniae in airway epithelial cells. , 2009, Pulmonary pharmacology & therapeutics.

[31]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[32]  S. Belaidi,et al.  A Conformational Exploration of Dissymmetric Macrolides Antibiotics , 2002 .

[33]  T. Henninger.  Recent progress in the field of macrolide antibiotics , 2003 .

[34]  N. Keicho,et al.  Macrolide Therapy in Chronic Inflammatory Diseases , 2012, Mediators of inflammation.

[35]  Fabrizio Giordanetto,et al.  Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. , 2014, Chemistry & biology.

[36]  Stephen P. Hale,et al.  The exploration of macrocycles for drug discovery — an underexploited structural class , 2008, Nature Reviews Drug Discovery.