Computational discovery of potent drugs to improve the treatment of pyrazinamide resistant Mycobacterium tuberculosis mutants

Abstract

Emergence of multi-drug resistance tuberculosis has become a serious health problem globally. Accumulation of mutations in the drug target led to the development of multi-drug resistant mycobacterial strains that have made most of the conventional drugs ineffective. Hence, there is desperate need for the development of new therapeutic strategies. Here, we focused on the analysis of mutations in Mycobacterium tuberculosis (Mtb) PncA (pyrazinamidase) that is responsible for resistance against first-line anti-tuberculosis pyrazinamide (PZA) drug. First, PZA and its two isoforms were analyzed for their binding affinity toward ligand binding cavity of Mtb wild-type and mutant PncA proteins. The observations suggested that some drug resistant mutations cause strong binding of PncA with the active form of PZA and impair its release, which is required to inhibit the growth of Mtb. To improve the treatment of PZA resistant Mtb, high throughput virtual drug screening was performed to identify potent drug molecules from a library of compounds derived from ChEMBL database. From this library, we predicted a lead molecule (terta-butyl(2S,4S)-4-amino-2-cyclopropyl-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate) to be more effective against PZA resistant Mtb strains in comparison to PZA. The lead molecule showed better drug-like properties such as high affinity and atomic interactions with wild-type and drug-resistant mutations in Mtb PncA proteins. Further, molecular dynamic simulation studies showed that this lead molecule has better conformational stability and compatibility with drug-resistant PncA proteins in comparison to PZA drug. We hypothesized that the predicted lead compound could be more effective, and thus may improve the treatment of PZA resistant tuberculosis.

In silico discovery and evaluation of phytochemicals binding mechanism against human catechol-O-methyltransferase as a putative bioenhancer of L-DOPA therapy in Parkinson disease

“…Upon verification, suitable drug-like property was confirmed in case of 63 phytochemicals (Supplemental Table 2) therefore structures of those phytochemicals were virtually screened against crystal structure of hCOMT within its known drug-binding site. VS technique has been revealed as a promising in silico procedure to identify potential lead compounds against any drug target [24,27,28,33,37]. VS result was proposed four phytochemicals such as withaphysalin M, withaphysalin N, withaphysalin F, and withaphysalin O (Supplemental Table 4) of plant W. somnifera with strong binding affinity against hCOMT.…”

“…Macromolecules are not static in nature, so their movement causes structural fluctuation with varying energies which may affect their relevant functional phenomena. MD simulation is the one and only computational method to study the functional behavior of biological molecules such as protein or enzyme in different thermodynamical condition with respect to time scales [24,33]. Here, we performed MD simulation to discover the time dependant structural fluctuation and functional stability of the enzyme human S-COMT (PDB ID: 3BWM) in the presence and absence of substrate SAM and the substrate analog DNC.…”

“…Here, we performed MD simulation to discover the time dependant structural fluctuation and functional stability of the enzyme human S-COMT (PDB ID: 3BWM) in the presence and absence of substrate SAM and the substrate analog DNC. Both of the MD run was performed independently for 50 ns using GROMOS96 54a7 force field of GROMACS 5.0.4 package [18,24,33]. Overall structural consistency and stability of the backbone folding pattern was observed from root mean square deviation (RMSD) plot (Fig.…”

Chemical reactivity and bioactivity properties of pyrazinamide analogs of acetylsalicylic acid and salicylic acid using conceptual density functional theory

“…Attaching the pyrazinamide moeity to salicylic and acetylsalicylic acid which belong to the class of aspirin drugs resulted to drug-likeness. Previous works [11,34,35,36] have used Molinspiration to provide the bioactivity properties. Figure 6 shows the bioactivity properties of the PZA analogs to a library of GPCR ligand, enzyme inhibitor, protease inhibitor, nuclear receptor ligand, kinase inhibitor and ion channel modulator.…”