3-D QSAR and Molecular Docking Studies on Aryl Benzofuran-2-yl Ketoxime Derivatives as Candida albicans N-myristoyl transferase Inhibitors

• Published in: QSAR & combinatorial science 2008-10, Vol.27 (10), p.1193-1203
• Main Authors: Telvekar, Vikas N., Kundaikar, Harish S., Patel, Kavit N., Chaudhari, Hemchandra K.
• Format: Article
• Language: English
• Subjects: 3-D QSAR; CaNMT; CoMFA; CoMSIA; CPH; PHASE
• ISSN: 1611-020X; 1611-0218
• DOI: 10.1002/qsar.200810017

3‐D QSAR studies were performed on aryl benzofuran‐2‐yl ketoxime derivatives. Pharmacophore Alignment and Scoring Engine (PHASE) was used to develop predictive Common Pharmacophore Hypotheses (CPHs) which were further validated. The alignment thus obtained was used for Comparative Molecular Field Analysis (CoMFA)/Comparative Molecular Similarity Indices Analysis (CoMSIA) model development. A structurally diverse set of 31 molecules was used of which 20 were grouped into training set to develop the model and the rest 11 molecules into test set to validate the CoMFA/CoMSIA models. The models so developed showed a good $\rm{ r_{{\rm{predictive}}}^{\rm{2}} }$ of 0.5973 for CoMFA and 0.5669 for CoMSIA. CoMFA and CoMSIA models had a Q2 (cross‐validated coefficient) of 0.518 and 0.460, respectively which showed high correlative and predictive abilities on both the test and training set. The 3‐D contour maps of CoMFA/CoMSIA provided interpretable explanation of SAR for the compounds and also permitted interesting conclusions about the substituent effects at different positions of the benzofuran‐2‐yl ketoximes derivatives. The docking studies were also carried out wherein the active and inactive molecules were docked into the active site of Candida albicans N‐myristoyl transferase (CaNMT) crystal structure to analyze the enzyme–inhibitor interactions. The results obtained from the present 3‐D QSAR and docking studies were used to design new predicted active molecules.