Identification of Novel Polyketide Synthase 13 of Mycobacterium Tuberculosis Inhibitors: A Modelling Approach Using the Pharmacophore Method -Based Virtual Screening

Abstract

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. It remains a major public health problem worldwide. In 2022, 10.6 million people contracted tuberculosis and 1.3 million died from it.  This manuscript presents our work, the aim of which is to find new inhibitors of Pks13, the enzyme responsible for the final stage in the synthesis of the mycolic acids that ensure the permeability and integrity of the Mtb cell wall.Using the computer-aided rational design method, a virtual library of 28,350 new benzofuran analogues was designed and then filtered using Lipinski's rule of five. After filtering, the reduced-size library obtained, which contained 5,194 benzofuran analogues, was screened using the PH4 inhibition of Pks13.At the end of the screening, the predicted activity of the molecules selected by PH4 was evaluated using the equation : ,QSAR model illustrating the linear correlation between experimental inhibition potential( )  and the Gibbs free energy with respect to a reference ligand( )in an aqueous medium. Analogues with greater predictive inhibitory activity than TAM2 (the most active ligand in the test set) and an excellent pharmacokinetic profile were identified. Of these new analogues, the most active had a predictive activity 96 times greater than that of TAM2.