title: Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis.
abstract: There is an urgent need for new drugs against tuberculosis which annually claims 1.7-1.8 million lives. One approach to identify potential leads is to screen in vitro small molecules against Mycobacterium tuberculosis (Mtb). Until recently there was no central repository to collect information on compounds screened. Consequently, it has been difficult to analyze molecular properties of compounds that inhibit the growth of Mtb in vitro. We have collected data from publically available sources on over 300 000 small molecules deposited in the Collaborative Drug Discovery TB Database. A cheminformatics analysis on these compounds indicates that inhibitors of the growth of Mtb have statistically higher mean logP, rule of 5 alerts, while also having lower HBD count, atom count and lower PSA (ChemAxon descriptors), compared to compounds that are classed as inactive. Additionally, Bayesian models for selecting Mtb active compounds were evaluated with over 100 000 compounds and, they demonstrated 10 fold enrichment over random for the top ranked 600 compounds. This represents a promising approach for finding compounds active against Mtb in whole cells screened under the same in vitro conditions. Various sets of Mtb hit molecules were also examined by various filtering rules used widely in the pharmaceutical industry to identify compounds with potentially reactive moieties. We found differences between the number of compounds flagged by these rules in Mtb datasets, malaria hits, FDA approved drugs and antibiotics. Combining these approaches may enable selection of compounds with increased probability of inhibition of whole cell Mtb activity.
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com and Collaborations In Chemistry, 601 Runnymede Avenue, Jenkintown, PA 19046, USA and Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, USA and Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.affiliation: Global Alliance for TB Drug Development, 40 Wall Street, 24th floor, New York, NY 10005, USA.
authors.forename: Takushi
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: 10 Connshire Drive, Waterford, Connecticut, 06385, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lipinski
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
authors.forename: Justin
authors.initials: J
authors.lastname: Bradford
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
authors.forename: Krishna
authors.initials: K
authors.lastname: Dole
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Spektor
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
authors.forename: Kellan
authors.initials: K
authors.lastname: Gregory
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
authors.forename: David
authors.initials: D
authors.lastname: Blondeau
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ernst
authors.affiliation: Division of Biocomputing, University of New Mexico, Albuquerque, NM 87131.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Yang
authors.affiliation: SureChem, The Macmillan Building, 4 Crinan Street, London, UKN1 9XW.
authors.forename: Nicko
authors.initials: N
authors.lastname: Goncharoff
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
authors.forename: Moses M
authors.initials: MM
authors.lastname: Hohman
authors.affiliation: Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Bunin
mesh_terms: D000995:Antitubercular Agents / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D001499:Bayes Theorem; D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D054852:Small Molecule Libraries