Abstract
α-Isopropylmalate Synthase (α-IPMS) encoded by leuA in Mycobacterium tuberculosis (M.tb) is involved in the leucine biosynthesis pathway and is extremely critical for the synthesis of branched-chain amino acids (leucine, isoleucine and valine). α-IPMS activity is required not only for the proliferation of M.tb but is also indispensable for its survival during the latent phase of infection. It is absent in humans and is widely regarded as one of the validated drug targets against Tuberculosis (TB). Despite its essentiality, any study on designing of potential chemical inhibitors against α-IPMS has not been reported so far. In the present study, in silico identification of putative inhibitors against α-IPMS exploring three chemical databases i.e. NCI, DrugBank and ChEMBL is reported through structurebased drug design and filtering of ligands based on the pharmacophore feature of the actives. In the absence of experimental results of any inhibitor against α-IPMS, a stringent validation of docking results is done by comparing with molecular mechanics/Poisson- Boltzmann surface area (MM/PBSA) calculations by investigating two more proteins for which experimental results are known.
Highlights
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M.tb)
Despite the availability of many treatment regimes, the global incidence of TB is still very high and it remains one of the top ten leading causes of death worldwide. 60% of the new cases reported in 2015 were from India, Indonesia, China, Nigeria, Pakistan and South Africa only, majority of which were due to reactivation of dormant bacilli residing inside the host
Transposon mutagenesis experiments and studies using leucine auxotroph have shown leucine biosynthetic pathway is essential for the growth and survival of M.tb [2]–[4]. α-Isopropylmalate Synthase (α-IPMS), encoded by leuA (Rv3710), catalyze the initial step of the leucine biosynthesis pathway, which involves Claisen condensation of acetyl coenzyme-A and α-ketoisovalerate (α-KIV) into αisopropylmalate (α-IPM) and coenzyme-A (CoA)
Summary
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M.tb). Three chemical libraries have been screened against α-IPMS to identify potential inhibitors using a hybrid virtual screening approach i.e. structure-based docking followed by filtering of ligands based on the pharmacophore features of the known active compounds. Molecular dynamics simulation has been performed to assess the result of docking and rescoring of ligands based on binding free energy (MM/PBSA) calculation.
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