Cell Wall Permeability Model Generation Using Chemoinformatics and Machine Learning Approaches.

The drug-resistant strains of () are evolving at an alarming rate, and this indicates the urgent need for the development of novel antitubercular drugs. However, genetic mutations, complex cell wall system of , and influx-efflux transporter systems are the major permeability barriers that significantly affect the drugs activity. Thus, most of the small molecules are ineffective to arrest the cell growth, even though they are effective at the cellular level. To address the permeability issue, different machine learning models that effectively distinguish permeable and impermeable compounds were developed. The enzyme-based (IC) and cell-based (minimal inhibitory concentration) data were considered for the classification of permeable and impermeable compounds. It was assumed that the compounds that have high activity in both enzyme-based and cell-based assays possess the required cell wall permeability. The XGBoost model was outperformed when compared to the other models generated from different algorithms such as random forest, support vector machine, and naïve Bayes. The XGBoost model was further validated using the validation data set (21 permeable and 19 impermeable compounds). The obtained machine learning models suggested that various descriptors such as molecular weight, atom type, electrotopological state, hydrogen bond donor/acceptor counts, and extended topochemical atoms of molecules are the major determining factors for both cell permeability and inhibitory activity. Furthermore, potential antimycobacterial drugs were identified using computational drug repurposing. All the approved drugs from DrugBank were collected and screened using the developed permeability model. The screened compounds were given as input in the PASS server for the identification of possible antimycobacterial compounds. The drugs that were retained after two filters were docked to the active site of 10 different potential antimycobacterial drug targets. The results obtained from this study may improve the understanding of permeability and activity that may aid in the development of novel antimycobacterial drugs.