Optimization of Structure Based Virtual Screening Protocols Against Thymidine Monophosphate Kinase Inhibitors as Antitubercular Agents

Thymidine monophosphate kinase from Mycobacterium tuberculosis (TMPK Mtub ) is an established drug target against tuberculosis. The enzyme TMPK Mtub is responsible for the survival of bacterium MTB and required to synthesize an essential building block of the bacterial DNA which is thymidine triphosphate (TTP). There are several potent inhibitors available against the target enzyme but the majority are substrate analogues. Recently, three dimensional structures of the enzyme TMPK Mtub inhibitor complexes were resolved using X‐ray crystallography. These available crystal structures were the basis of initiating a structure based lead identification campaign against TMPK Mtub . The available information was utilized to perform structure‐based virtual screening against TMPK Mtub with the hope to diversify the structures of the current inhibitors. In order to setup the protocol, 10 000 out of 45 000 drug‐like molecules were randomly selected from National Cancer Institute’s (NCI) database. Additionally 105 known inhibitors along with 11 natural substrates were mixed with the 10 000 selected compounds. For the current study, a rigid based docking algorithm, i.e., FRED has been utilized to set up an efficient docking and scoring protocol. The methods including enrichment curves, consensus scoring and ROC curves are providing useful insights into the setting up of a suitable structure‐based docking protocol against TMPK Mtub . As a result, an optimum docking and scoring function has been identified for future large scale virtual screening. In the present work, we have demonstrated a rational choice of protocol for structure based virtual screening of chemical libraries and help to understand the influence of receptor flexibility by using multiple geometries.