Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis.
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.
Ekins
Sean
S
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.
Kaneko
Takushi
T
Global Alliance for TB Drug Development, 40 Wall Street, 24th floor, New York, NY 10005, USA.
Lipinski
Christopher A
CA
10 Connshire Drive, Waterford, Connecticut, 06385, USA.
Bradford
Justin
J
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
Dole
Krishna
K
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
Spektor
Anna
A
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
Gregory
Kellan
K
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
Blondeau
David
D
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
Ernst
Sylvia
S
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
Yang
Jeremy
J
Division of Biocomputing, University of New Mexico, Albuquerque, NM 87131.
Goncharoff
Nicko
N
SureChem, The Macmillan Building, 4 Crinan Street, London, UKN1 9XW.
Hohman
Moses M
MM
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
Bunin
Barry A
BA
Collaborative Drug Discovery, 1633 Bayshore Highway, Suite 342, Burlingame, CA 94010. sekins@collaborativedrug.com ekinssean@yahoo.com.
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*
D000995:Antitubercular Agents; D054852:Small Molecule Libraries