Building small molecules with YASARA

In YASARA Model and above, a sophisticated small molecule builder is available to construct your molecules manually in just a few seconds. (Alternatively, automatic building from SMILES strings is supported in all YASARA stages, and larger molecules can be built from their sequence).

Movie 1 on the top right shows how building works in practice, drawing on the example of tiotropium, an anti-asthmatic bronchodilator known as 'Spiriva', which is also shown in the bottom right figure 2. Interactive building is an iterative process, where you select hydrogen atoms that should be replaced or bridged with functional groups. YASARA provides over 50 groups to choose from, each with up to four alternative attachment points. As known from 2D molecule editors, you can simply 'write' new atoms and adapt bonds by typing on the keyboard, e.g. click on a hydrogen and type 'C' to turn it into a CH3 group, or 'O' to turn it into an OH group (hydrogens are thus added automatically).

It is also worth mentioning that YASARA can record user input as a macro, generating the following code while building the tiotropium in movie 1 (comments have been added manually):

# Start with a 7-ring 
BuildGroup Cycloheptyl 
# Add nitrogen bridge 
BridgeAtom 9,18,Nitrogen 
# Add two methyl groups to nitrogen bridge 
SwapAtom 18 19,Carbon,UpdateBonds=yes,UpdateHyd=yes 
# Add oxygen bridge 
BridgeAtom 11,14,Oxygen 
# Add ester 
SwapAtom 1,Ester,AttachPoint=2 
# Add methyl group 
SwapAtom 1,Carbon,UpdateBonds=yes,UpdateHyd=yes 
# Add hydroxyl group 
SwapAtom 2,Oxygen,UpdateBonds=yes,UpdateHyd=yes 
# Add thiophene rings 
SwapAtom 4 5,Pyrryl,AttachPoint=2 
SwapAtom 5 14,Sulfur,UpdateHyd=yes 

The screenshot in the middle is from the help movie "4.1 Building small molecules", which starts with an easier example (4-Iododiazenyl- 8-methyl- pyromellitimide) and then continues with tiotropium.

The molecule builder makes extensive use of YASARA's knowledge about pH-dependent bond orders and protonation states. Having built the molecule, you can proceed to optimize its geometry, either semi-empirically using the built-in MOPAC, or empirically with automatic force field parameter assignment using YASARA AutoSMILES.