Arabinosyl transferase inhibitor design against Mycobacterium tuberculosis using ligand based drug design approach

Result and Discussion

Herein, we have screened out 3148 compounds structurally similar with ethambutol from 11,74,583 compounds based on chemical similarity (structural) using ZINC database. We have also retrieved ethambutol like 5 compounds from Chemspider on the basic of calculated property, 10 from ChemBank on the basic of substructure and 3 from Pubchem on the basic of property. We calculated physicochemical property for 222 compounds in Molsoft ICM-Browser software and observe that most of the compounds follows Lipinski’s rule of Five as presented in the Table I including few analogues of ethambutol.

Table I: Physicochemical property of top ranking database compounds

The compounds with the predicted drug likeness of more than 80% with Lipinski’s qualification were used to study their ADME properties. 222 compounds were checked for absorption and distribution in human body using PreADMET as given in Table II. Each compound was checked for carcinogenic, embryo toxin and teratogenic and 31 non-toxic compounds were chosen for molecular docking analysis.

Table II: ADME of compounds

Table III: Predicted binding sites of the receptor

Receptor model was exported and potential bindings sites were predicted in the Molegro Virtual Docker workspace as presented in the Table III with their coordinate position in the workspace. Missing coordinates of receptor was checked before loading. Amino acid residues around the binding cavity were given in the Table IV.

Table IV: Amino acid residues around the  potential binding site

Molecular docking is a novel approach to study small compound inhibition to receptor protein. We docked 31 non toxic compounds with receptor model of M. tuberculosis arabinosyl transferase using Molegro Virtual Docker (MVD) software. MVD is molecular visualization and molecular docking software which is based on a differential evolution algorithm; the solution of the algorithm takes into account the sum of the intermolecular interaction energy between the ligand and the protein and the intramolecular interaction energy of the ligand. The docking energy scoring function is based on the modified piecewise linear potential (PLP) with new hydrogen bonding and electrostatic terms included.

The ligands were optimized before docking for proper structural stabilization. We calculated stretch, bend, steth bend, torsion, non-1,4 VDW, 1,4 VDW, total energy (Kcal/mol) using MM2 module of Chembio office tool. Docking computation was done based on the parameters mentioned in the methodology.

While docking the receptor was set rigid and docked with the receptor binding site inside the constraint  (Figure 1 and Figure 2) where, bond flexibility of lignds was set as ‘on’. The docking result has predicted two database compounds and two analogues of ethambutol based on least energy score of   rerank, moldock and H bond values as presented in the Table V. Dock poses were further inspected for hydrogen bonding interaction with the receptor.

Table V: Docking result

Figure 1: Predicted cavities of arabinosyl transferase

Figure 2: Receptor-ligand H bond interaction

The compound Chemspider20572082 and Zinc00388344 showed highest rerank score of -117.9 and -107.3 with optimum hydrogen bonding with the receptor including two analogue of ethambutol as shown in the Table VI.

Table VI: Hydrogen bonding between ligands and receptor

The compound Chemspider20572082 interacts with the amino acid residue Gly1058, Asp1052 and Asp1056 and forming three hydrogen bond interaction at the distance of 2.43, 2.35 and 1.99 Ã… respectively. ZINCOO388344 is forming three hydrogen bonds with Val1045 and Leu1060 and clearly reflecting its novelty as a inhibitor of M. tuberculosis arabinosyl transferase in compared with ethambutol  having poor reranking score of -39.980.

Screening for alternative and effective drug is urgently needed to combat the drug resistance straings of M. tuburculosis (Burris, 2004; McIlleron et al., 2009; Zhang et al., 2014). The failure of ethambutol is another challenge. Therefore to meet the present challenges for inhibition of M. tuberculosis arabinosyl transferase by these compounds would be a useful starting point to design better therapeutics of M. tuberculosis and in vitro experiment on compounds, viz. Chem2057082 and ZINCOO388344 is recommended.

In this investigation, virtual screening has been performed using various filters. The screened compounds are subjected to molecular docking and result are analysis on the basic of rerank score and hydrogen bond interaction and it was found that 3 compounds showed better result out of 31 docked compound than the control drug. Further ADME and pharmacological effects of these compounds observed comparatively better bioavailability, distribution, absorption, drug likeness, and pharmacological effects than ethambutol. Hence, it could be concluded that these three compounds could be considered as potent drug candidate of M. tuberculosis.

Acknowledgement

The authors thankfully acknowledge the Department of Biotechnology (DBT), Govt. of India for providing the Bioinformatics Infrastructure Facility (BIF) to CSIR-NEIST, Jorhat under the project ‘Creation of BIF for the promotion of biology teaching through bioinformatics, 2008’.