A computational protocol for the discovery of lead molecules targeting DNA unique to pathogens

Abstract

With the rapid emergence of drug resistant pathogens, it has become imperative to develop alternative medications as well as find new drug targets to overcome this crisis. Hence, this has become prime focus of several academic laboratories and pharmaceutical companies. Here, we report a computational protocol for identifying unique DNA sequence(s) in the pathogen which is absent in human and related non-pathogenic strains of the microbe. In order to use the unique sequence as drug target, the protocol, in the second step, uses virtual screening against a million compound library to identify candidate small molecules which can bind to these unique DNA targets in the pathogen only. Theoretically the molecules identified after screening should not bind to human DNA. This methodology is demonstrated on Mycobacterium tuberculosis H37Rv, wherein a new octamer sequence present only in H37Rv has been identified and a few candidate small molecules as potential drug have been proposed. Being fast and cost effective, this protocol could be of importance in generating new potential drug candidates against infectious organisms for further experimental studies. This methodology is freely available at http://www.scfbio-iitd.res.in/PSDDF/.

Keywords: Comparative genomics; Computational protocol; DNA-ligand docking; Genome comparison; Rapid screening; Unique pathogenic DNA motif.