3D-QSAR and molecular modeling studies on 2,3-dideoxy hexenopyranosid-4-uloses as anti-tubercular agents targeting alpha-mannosidase

• 3D-QSAR analyses with CoMFA and CoMSIA on a set of hexenopyranosidulose analogues.
• Homology modeling of alpha-mannosidase was used for molecular docking studies.
• Molecular dynamics simulation give insight into the rationale for binding affinity of inhibitors.
• Comprehensive information will help for structure-guided design of more potent analogues as anti-tubercular agents.

Ligand-based and structure-based methods were applied in combination to exploit the physicochemical properties of 2,3-dideoxy hex-2-enopyranosid-4-uloses against Mycobacterium tuberculosis H37Rv. Statistically valid 3D-QSAR models with good correlation and predictive power were obtained with CoMFA steric and electrostatic fields (r2 = 0.797, q2 = 0.589) and CoMSIA with combined steric, electrostatic, hydrophobic and hydrogen bond acceptor fields (r2 = 0.867, q2 = 0.570) based on training set of 33 molecules with predictive r2 of 0.808 and 0.890 for CoMFA and CoMSIA respectively. The results illustrate the requirement of optimal alkyl chain length at C-1 position and acceptor groups along hydroxy methyl substituent of C-6 to enhance the anti-tubercular activity of the 2,3-dideoxy hex-2-enopyranosid-4-uloses while any substitution at C-3 position exert diminishing effect on anti-tubercular activity of these enulosides. Further, homology modeling of M. tuberculosis alpha-mannosidase followed by molecular docking and molecular dynamics simulations on co-complexed models were performed to gain insight into the rationale for binding affinity of selected inhibitors with the target of interest. The comprehensive information obtained from this study will help to better understand the structural basis of biological activity of this class of molecules and guide further design of more potent analogues as anti-tubercular agents.

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