Prediction of novel and potent inhibitors of lanosterol 14-α demethylase

Abstract

Lanosterol 14-α demethylase (LDM) is one of the promising drug targets of azoles antifungal. In this study, we have screened a large number of small molecules from different chemical databases (ZINC, DrugBank, ChEMBL, and ChemDiv) to find out novel and potential inhibitors of LDM. As a result, from more than a hundred thousand molecules, the two best candidates, C1 (ZINC000299817826) and C3 (ZINC000095786149), were selected from the top-scoring compounds and further validated in Molecular Dynamic (MD) simulation. The Glide scores of C1 and C3 were −19.33 kcal/mol and −19.13 kcal/mol, suggesting that these compounds bind with LDM with higher binding affinity than the benchmark compound (itraconazole), which has a Glide score of −6.85 kcal/mol. Docking poses reveal that the compounds C1 and C3 bind to the outermost region of the LDM binding site, which can prevent the lanosterol from getting into the catalytic pocket. Furthermore, MD simulation studies were performed to assess the stability of C1 and C3 in complex with LDM and were found to be stable over the 100 nanosecond simulation time. Binding free energy calculated by the MMPBSA method suggested that the C3 forms a more stable complex with the LDM as close to the benchmark compounds. Among the top selected molecules, C1 and C3 were predicted to be the significant inhibitors of LDM.

Communicated by Ramaswamy H. Sarma

Keywords:

• Lanosterol 14-α demethylase
• molecular docking
• molecular dynamic simulation
• virtual screening
• free energy calculation
• phytochemical

Acknowledgment

MW and NS acknowledge the support of the School of Computational and Integrative Sciences, Jawaharlal Nehru University, for providing all the necessary facilities for carrying out the research work. MW is supported by the Indian Council of Medical Research (ICMR) as Senior Research Fellowship. MW and JKT acknowledge support from the National Institute of Plant Genome Research and the International Centre for Genetic Engineering and Biotechnology.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

Bioinformatics infrastructure facility at our school funded by the Department of Biotechnology of Government of India and Mohd Waseem as a Senior Research Fellow supported by Indian Council of Medical Research, New Delhi, India.