Computational design of drugs for Epilepsy using a novel guided evolutionary algorithm for enhanced Blood Brain Barrier permeability

Epilepsy is a common disorder of the Central Nervous System. Although several drugs are available for treatment of epilepsy, none of them are applicable for all cases, and some have serious adverse affects. The rational design of small molecule drugs for disorders of the Central Nervous System is a difficult process because the majority of small molecules are unable to cross the Blood- Brain-Barrier. Although many methods have been developed for computer aided drug design, only a few of these are focused on the specific requirements of Central Nervous System drugs. To address these limitations, a validated free and open source drug design package, Autogrow4, was modified to guide the evolution of the population, for generation of molecules with improved permeability across the Blood-Brain-Barrier. This method has the potential for application in computer aided drug design for other Central Nervous System disorders such as Addiction, Alzheimer’s disease, Bipolar disorder, Depression, Gliomas, and Tuberculous meningitis. This method was applied for the design of inhibitors of g-Amino Butyric Acid Transaminase, which is a validated target for the treatment of epilepsy. The ligands designed with this method were predicted to have high binding affinity for the target as well as high permeability across the Blood-Brain-Barrier. The designed molecules were assessed by using the SWISS-ADME webserver which predicted that the designed molecules were Blood-Brain-Barrier permeable, did not have any violation of Lipinsky’s rules and were chemically synthesizable.