Parameters

File Options

-log

The argument for this flag specifies the name of the log file. The level of detail for logfile information can be altered using the -verbose flag. Generation of an output log may be disabled by providing nul as a argument in Windows and /dev/null as an argument on Linux and macOS. [default = prefix _log.txt]

-prefix

The argument for this flag defines the prefix to be used for various information and data files generated. Most important among these is the ‘prefix_parm.txt’ file which includes a copy of all the parameters used in the run. The prefix is also used to generate a default log file name if not explicitly specified with the -log flag. [default = <app_name>].

-verbose

This is a boolean flag that controls the level of detail written to the log file. By default only minimal information is written to the log file. Verbose logging will cause more information to be written to the log file in order to follow behavior during program execution. [default = false]

-molNames

This parameter takes a text file containing a list of molecule names (one name per line in the file). If this parameter is set then only molecules in the input file(s) (see parameter -in) with names that match those in the text files will be read in.

The general purpose of this flag is to provide an easy mechanism for reading a few specific molecule(s) that are contained in a large file, without having to extract those molecules by hand from the input molecules file. [default = NONE].

-in (-qMol, -queryMol)

Molecular file encapsulating the query. It contains the primary molecule of interest, the query fragment, description of the query potential function and constraints, and the protein structures for the active site and for selectivity.

-out (-o)

Output filename to be generated. Accepted file formats are: cxsmiles, ism, mol2, oeb, oez, sdf, smi.

Execute Options

-param

The argument for this flag is the name of a file containing control parameters. The control parameter file acts to either replace or augment the command line interface. All parameters necessary for program execution may be provided in the control parameter file, although any command given explicitly on the command line will supersede options found in the parameter file. The application generates a new parameter file containing the full set of execution parameters upon every execution. The name of the parameter file is created by combining the prefix base name with the ‘_parm’ suffix and the ‘.txt’ extension.

-mpi_np <n>

Specifies the number of processors n when the application is run in MPI mode.

-mpi_hostfile <filename>

Specifies the name of the file containing the processor’s configuration. For every host, this file should contain a line host_name slots=n where n is the number of processors on the host.

BROOD App Options

-db (-database)

Specified the directory containing the BROOD database files. Additional details on the files contained in the directory can be found in the section on the Fragment Database.

-cpddb

The user can specify a file of available compounds (either commercial or internal) with this flag. If specified, molecules from this file that are similar to any created analogs will be used to annotate the newly suggested molecule. More details about analog similarity is described in Similarity to available compounds method.

-quickLook <n> (-quick)

This flag allows a user to do a quick BROOD search (in n number of seconds). BROOD is designed to identify as many interesting hits as soon as possible. Thus while a thorough search may take minutes to hours, useful preliminary results can be generated in approximately n seconds with this option.

BROOD Hit List Builder Options

-idea (-cluster)

This flag determines if the hit list will be organized according to a reduced graph hierarchy. This is quite useful for clustering similar analogs and thus allowing a user to quickly scan the different analog families and drill down into the most interesting clusters without needing to examine hundreds of analogs. [default = true]

-maxHits (-maxHit)

This flag determines the number of compounds saved in the hit list. Allowable range is 1–50000. The legal range of this parameter has been increased by an order of magnitude. [default = 1000]

-buildType

This flag determines the type of building to perform. Accepted values are 2d (2 dimensional build), noopt3d (3 dimensional build without optimization), and optimized (3 dimensional build with optimization). [default = optimized]

-checkBond

If this flag is set to True, BROOD will check all bonds formed between new fragments and the rest of the query molecule and eliminate fragments that form bond types that are typically unstable. Rather than being discarded entirely, these hits will be written in the brood_removed.oeb.gz file by default. [default = true]

-deltaLocalStrain

Boolean flag indicating if the relative local strain between query and analog should be used as a measure of strain. [default = false]

-maxLocalStrain

Maximum local strain allowed to fit an analog molecule on top of a query. [default = 6.5]

-neutralpH

This flag controls whether the final molecules are set to an ionization state suitable at pH=7.4. Because new bonds are formed in the process of generating analogs, functional groups sometimes need adjustment even if their state was properly normalized prior to fragmentation. This flag allows the user to turn off pKa normalization. [default = true]

-tautomers (-tautomer)

Similarly, the -neutralpH adjustment of tautomer states can be necessary after joining the new fragments with the static portions of the original molecule. This flag allows the user to turn off this normalization. [default = true]

BROOD Match Options

-attachCutoff  (-attachmentCutoff, -attachCut)

Minimum acceptable attachment point score cutoff. The cutoff is for the shape overlap score of the beginning and ending atom of each attachment bond. The default was chosen empirically to assure all fragments in the hit list would have sensible attachment geometries. This value does not affect runs when the -scoreType flag is set to linkOnly. [default = 0.78]

-bondOrder (-bo)

When this Boolean flag is set, only fragments with the same attachment bond orders as the query fragment are allowed. [default = true]

chargeType (-fileChrg)

When this flag is set to fileChrg, the partial charges for electrostatic Tanimoto calculations are taken from the input files. If this flag is set to mmff94, or the input file does not contain partial charges, MMFF94 charges will be used. The partial charges on the database molecules are pregenerated. [default = mmff94]

-checkGeometry

By default, regardless of the attachment score (used primarily to drive the optimization), the fit of a fragment at the attachment points is controlled by geometric constraints. These require that the two attachment vectors that will be jointed into a bond are overlapping and pointing in roughly opposite directions. In some cases, particularly when the required geometry is unusual or strained, it can be useful to turn off this constraint check. [default = true]

-property (-prop)

This Boolean flag indicates whether ANY of the molecular properties should be used to eliminate compounds from consideration. While these filters can be useful, if a user expects to see a particular fragment or analog and it does not appear in the hit list, it will often have been eliminated by the property filters. The Report Files will indicate which, if any, property filter affected each fragment. If set to false, all of the related flags below become irrelevant. [default = false]

-ringOnly (-ring)

This is a complex flag whose purpose is to allow the user to control the number of ring atoms in the selected fragments. It allows input of “-2, -1, 0, or an integer 1 <= x <= 12”. This flag has to do with a count of the number of ring atoms in the shortest path between attachment points in a fragment. In cases with more than two attachment points, all shortest paths are calculated and the number of ring atoms is summed.

By default, the flag is set to “-2” (true) and requires at least two ring atoms in the path. If the flag is set to “0” (false), no ring atom filtering is done, while if the flag is set to “-1” (none), only fragments without ring atoms in the shortest paths are returned. If the flag is set to a number between 0 and 13, then that will be the minimum number of ring atoms required. [default = -2]

-shapeCutoff

Indicates the minimum required shape Tanimoto score required for a fragment to appear in the color, elect, or queryAnalog hit lists. This cutoff is useful for cases when few shape-similar fragments exist in the database being searched. [default = 0.6]

BROOD Score Options

-attachScale (-attachmentScale, -attach, -aScale)

This floating point value determines the balance between the chemical color score and the attachment point scores. Higher values indicate more weighting for the attachment-point alignment. This parameter has complex effects; please use it with care. [default = 1.5]

-bumpRadius

This real number flag determines the minimum distance between ligand heavy atoms and protein heavy atoms in the final relaxed solution for there to be considered a clash. New analogs with atoms closer than this cutoff to the active site protein are discarded from the hit list. If a selectivity protein is being used, at least one clashing atom must be found in order for the hit list ligand to be retained. Because the molecular model of the protein is rigid, it may be advantageous for this cutoff to be shorter than in a system with a flexible protein model. [default = 2.25]

-ignoreProtein (-noqueryprot, -noqueryprotein)

When a query is created with the GUI and an active site protein is included, the section active site protein becomes part of the query. This flag makes BROOD ignore the active site protein even though it is part of the query. The flag makes it easy to run the BROOD job with and without the active site protein. [default = false]

-ignoreProteinSelect (-noqueryselectionprotein, -noqueryselection)

When a query is created with the GUI and a selectivity protein is included, the selectivity protein becomes part of the query. This flag makes BROOD ignore the selectivity protein even though it is part of the query. The flag makes it easy to run the BROOD job with and without the selectivity protein. [default = false]

-rangeOffset

By default, the range of fragment heavy atoms specified by the -rangeSize flag is centered around the same number of heavy atoms as the original query fragment. Instead, the user can use this flag to bias a search toward smaller or larger fragments with positive or negative values passed to this flag. [default = 0]

-rangeSize

By default, only fragments with a number of heavy atoms +/- N from the fragment being replaced are considered. This flag lets the user control this setting. It should not be necessary to change this value except in unusual circumstances. This flag determines the range of heavy atoms around query fragment’s number of heavy atoms to examine. [default = 6]

-scoreType

This flag can have three legal values: rocs, et, and linOnly. If set to rocs, the shape and color Tanimoto similarities are calculated. If set to et, the electrostatic Tanimoto similarity is calculated on all of the fragments that also have a good shape score. If this flag is set to linkOnly, then the shape and chemistry of the fragment are ignored and ONLY the attachment point geometry (and constraints) are used to identify similar fragments. This is similar to Bartlett’s Caveat algorithm, one of the first algorithms in this genre. This type of search can be useful when trying to bridge one or more fragments without any prior knowledge, such as when linking two fragments in fragment-based design.[default = rocs]

Molecule Property Options

-eganEgg (-egan)

This Boolean parameter determines whether analog compounds will be required to fulfill the “Egan egg” measure of bioavailability. This measure was published by Bill Egan while at Pharmacopia [Egan-2000], and rejects compounds with a LogP > 5.88 or a PSA > 131.6. [default = true]

-veber (-gsk)

This Boolean parameter determines whether analog compounds will be required to fulfill the measure of bioavailability Veber published at GSK [Veber-2002]. His measure of bioavailability eliminates compounds with a PSA > 140 or more than 10 rotatable bonds. [default = false]

Extrinsic Property Values

-minAcceptors (-minLipinskiAcceptors, -minLipinskiAcc)

-maxAcceptors (-maxLipinskiAcceptors, -maxLipinskiAcc)

These flags indicate the upper and lower bound of the Lipinski hydrogen bond acceptor range of any analog. Analogs higher or lower in number of Lipinski hydrogen bond acceptors than these cutoffs will be eliminated from consideration. For the purpose of this measure, hydrogen bond acceptors are determined by the method of Lipinski [Lipinski-1997]. [default = 2, 11]

-minComplexity (-minComp)

-maxComplexity (-maxComp)

These flags indicate the upper and lower bound of the molecular complexity range of any analog. Analogs higher or lower in molecular complexity than these cutoffs will be eliminated from consideration. For more on molecular complexity, please see the theory section. [default = 0.0, 2.5]

-minDonors (-minLipinskiDonors, -minLipinskiDon)

-maxDonors (-maxLipinskiDonors, -maxLipinskiDon)

These flags indicate the upper and lower bound of the Lipinski hydrogen bond donor range of any analog. Analogs higher or lower in number of Lipinski hydrogen bond donors than these cutoffs will be eliminated from consideration. For the purpose of this measure, hydrogen bond donors are determined by the method of Lipinski [Lipinski-1997]. [default = 1,8]

-minFrequency (-minFreq)

-maxFrequency (-maxFreq)

These flags indicate the upper and lower bound of the frequency range of any analog. Analogs higher or lower in frequency than these cutoffs will be eliminated from consideration. For the purpose of this calculation, the frequency is a percentile number indicating the frequency of each fragment normalized relative to the frequency of fragments in ChEMBL. Frequency as assessed here is a measure of how common each fragment is among the source molecules. The most commonly occurring fragment would be in the 99th percentile, while the least commonly occurring fragments would be in the 1st percentile. [default = 0, 100]

-minLipinski

-maxLipinski

These flags indicate the upper and lower bound of the Lipinski violations range of any analog. Analogs higher or lower in number of Lipinski violations than these cutoffs will be eliminated from consideration. [Lipinski-1997]. In Lipinski’s work, in order to segregate molecules that progressed through clinical trials, he determined that one violation was acceptable, but two were not. [default = 0, 1]

-minlogp

-maxlogp

These flags indicate the upper and lower bound of the calculated LogP range of any analog. Analogs higher or lower in LogP than these cutoffs will be eliminated from consideration. [default = -1.0,5.0]

-minMartin (-minAbbott, -minABS)

-maxMartin (-maxAbbott, -maxABS)

These flags indicate the upper and lower bound of the Abbott Bioavailability Score (ABS) range of any analog. Analogs higher or lower in ABS than these cutoffs will be eliminated from consideration. This floating point ABS parameter (range 0.0-1.0) indicates the minimum allowable probability that F will be >10% in rats according the QSAR model developed and published by Yvonne Martin [Martin-2005]. A value of 0.0 will allow all compounds to pass. [default = 0.2, 1.0]

Intrinsic Property Values

-minAromFJCt

-maxAromFJCt

These flags indicate the upper and lower bound of the aromatic ring range of any analog. Analogs higher or lower in number of aromatic rings than these cutoffs will be eliminated from consideration. For the purpose of this calculation, the number of aromatic rings is the number of aromatic rings is #aromatic bonds - #aromatic atoms + 1. [default = 0, 5]

-minFsp3C

-maxFsp3C

These flags indicate the upper and lower bound of the fraction of carbons that are sp³ range of any analog. Analogs higher or lower in the fraction of carbons that are sp³ than these cutoffs will be eliminated from consideration. There is some evidence that increasing the fraction of carbons in a series that are sp³ (escaping from “Flatland”) improved success in clinical trials [Lovering-2009]. [default = 0.3, 1.0]

-minHvyAtom (-minHeavyAtom)

-maxHvyAtom (-maxHeavyAtom)

These flags indicate the upper and lower bound of the heavy atom range of any analog. Analogs higher or lower in number of heavy atoms than these cutoffs will be eliminated from consideration. [default = 7,35]

-minMolWt (-minmolecularweight)

-maxMolWt (-maxmolecularweight)

These flags indicate the upper and lower bound of the molecular weight range of any analog. Analogs higher or lower in molecular weight than these cutoffs will be eliminated from consideration. [default = 100,500]

-minRotBond (-minRotatableBond)

-maxRotBond (-maxRotatableBond)

These flags indicate the upper and lower bound of the rotatable bond range of any analog. Analogs higher or lower in number of rotatable bonds than these cutoffs will be eliminated from consideration. [default = 0,13]

-minpsa (-mintpsa)

-maxpsa (-maxtpsa)

These flags indicate the upper and lower bound of the topological polar surface area (TPSA) range of any analog. Analogs higher or lower in TPSA than these cutoffs will be eliminated from consideration. [Clark-1999] [Ertl-2000]. [default = 60,150]