Cheminformatics-based enumeration and analysis of large libraries of macrolide scaffolds

We report on the development of a cheminformatics enumeration technology and the analysis of a resulting large dataset of virtual macrolide scaffolds. Although macrolides have been shown to have valuable biological properties, there is no ready-to-screen virtual library of diverse macrolides in the public domain. Conducting molecular modeling (especially virtual screening) of these complex molecules is highly relevant as the organic synthesis of these compounds, when feasible, typically requires many synthetic steps, and thus dramatically slows the discovery of new bioactive macrolides. Herein, we introduce a cheminformatics approach and associated software that allows for designing and generating libraries of virtual macrocycle/macrolide scaffolds with user-defined constitutional and structural constraints (e.g., types and numbers of structural motifs to be included in the macrocycle, ring size, maximum number of compounds generated). To study the chemical diversity of such generated molecules, we enumerated V1M (Virtual 1 million Macrolide scaffolds) library, each containing twelve common structural motifs. For each macrolide scaffold, we calculated several key properties, such as molecular weight, hydrogen bond donors/acceptors, topological polar surface area. In this study, we discuss (1) the initial concept and current features of our PKS (polyketides) Enumerator software, (2) the chemical diversity and distribution of structural motifs in V1M library, and (3) the unique opportunities for future virtual screening of such enumerated ensembles of macrolides. Importantly, V1M is provided in the Supplementary Material of this paper allowing other researchers to conduct any type of molecular modeling and virtual screening studies. Therefore, this technology for enumerating extremely large libraries of macrolide scaffolds could hold a unique potential in the field of computational chemistry and drug discovery for rational designing of new antibiotics and anti-cancer agents.

[1]  Gavin J. Williams.  Engineering polyketide synthases and nonribosomal peptide synthetases. , 2013, Current opinion in structural biology.

[2]  Piotr Dittwald,et al.  Efficient Syntheses of Diverse, Medicinally Relevant Targets Planned by Computer and Executed in the Laboratory , 2018 .

[3]  Dušanka Janežič,et al.  BoBER: web interface to the base of bioisosterically exchangeable replacements , 2017, Journal of Cheminformatics.

[4]  W. L. Jorgensen.  The Many Roles of Computation in Drug Discovery , 2004, Science.

[5]  S. Schreiber,et al.  Macrolactones in diversity-oriented synthesis: preparation of a pilot library and exploration of factors controlling macrocyclization. , 2004, Journal of combinatorial chemistry.

[6]  Brian K. Shoichet,et al.  Virtual screening of chemical libraries , 2004, Nature.

[7]  S. Pandeya,et al.  Combinatorial Chemistry: A Novel Method in Drug Discovery and Its Application , 2005 .

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

[9]  George Papadatos,et al.  Beyond the hype: deep neural networks outperform established methods using a ChEMBL bioactivity benchmark set , 2017, bioRxiv.

[10]  C. Heinis,et al.  Drug discovery: tools and rules for macrocycles. , 2014, Nature chemical biology.

[11]  Hans-Joachim Böhm,et al.  A guide to drug discovery: Hit and lead generation: beyond high-throughput screening , 2003, Nature Reviews Drug Discovery.

[12]  Andreas Kirschning,et al.  Merging chemical synthesis and biosynthesis: a new chapter in the total synthesis of natural products and natural product libraries. , 2012, Angewandte Chemie.

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

[14]  Gavin J. Williams,et al.  Promiscuity of a modular polyketide synthase towards natural and non-natural extender units. , 2013, Organic & biomolecular chemistry.

[15]  Edward W. Lowe,et al.  Computational Methods in Drug Discovery , 2014, Pharmacological Reviews.

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

[17]  Andrei K. Yudin,et al.  Macrocycles: lessons from the distant past, recent developments, and future directions , 2014, Chemical science.

[18]  Heinz G Floss,et al.  Combinatorial biosynthesis--potential and problems. , 2006, Journal of biotechnology.

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

[20]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[21]  Kristina Luthman,et al.  Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans , 1997, Pharmaceutical Research.

[22]  Screening and Identification of Structural Analogs of GW9662 and T0070907 Potent Antagonists of Peroxisome Proliferator-Activated Receptor Gamma: In-Silico Drug-Designing Approach , 2017 .

[23]  É. Marsault,et al.  Macrocycles are great cycles: applications, opportunities, and challenges of synthetic macrocycles in drug discovery. , 2011, Journal of medicinal chemistry.

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

[25]  M. J. Gardner,et al.  COMBINATORIAL SYNTHESIS : THE DESIGN OF COMPOUND LIBRARIES AND THEIR APPLICATION TO DRUG DISCOVERY , 1995 .

[26]  Michael G Thomas,et al.  Biosynthesis of polyketide synthase extender units. , 2009, Natural product reports.

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

[28]  David R. Liu,et al.  Translation of DNA into a library of 13,000 synthetic small-molecule macrocycles suitable for in vitro selection. , 2008, Journal of the American Chemical Society.

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

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

[31]  A. P. Sergeyko,et al.  Rational design of macrolides by virtual screening of combinatorial libraries generated through in silico manipulation of polyketide synthases. , 2006, Journal of medicinal chemistry.

[32]  C. Khosla,et al.  Combinatorial biosynthesis of polyketides--a perspective. , 2012, Current opinion in chemical biology.

[33]  N. Terrett,et al.  Methods for the synthesis of macrocycle libraries for drug discovery. , 2010, Drug discovery today. Technologies.

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

[35]  Jonathan Kennedy,et al.  Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosynthetic engineering for diversifying natural products. , 2008, Natural product reports.

[36]  M. Maier,et al.  Design and synthesis of analogues of natural products. , 2015, Organic & biomolecular chemistry.

[37]  P. Seneci,et al.  Drugs against avian influenza a virus: design of novel sulfonate inhibitors of neuraminidase N1. , 2014, Current pharmaceutical design.

[38]  Bradley C Doak,et al.  How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets. , 2016, Journal of medicinal chemistry.

[39]  Bradley C Doak,et al.  Cell permeability beyond the rule of 5. , 2016, Advanced drug delivery reviews.

[40]  Dianqing Sun,et al.  Macrocyclic Drugs and Synthetic Methodologies toward Macrocycles , 2013, Molecules.

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

[42]  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.

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

[44]  M. J. Gardner,et al.  Combinatorial Synthesis ‐ The Design of Compound Libraries and Their Application to Drug Discovery , 1995 .