Discovery of New Antifungal Leads via Pharmacophore Modeling and QSAR Analysis of Fungal N-Myristoyl Transferase Inhibitors Followed by In Silico Screening

• Published in: Chemical biology & drug design 2011-09, Vol.78 (3), p.391-407
• Main Authors: Taha, Mutasem O., Qandil, Amjad M., Al-Haraznah, Tariq, Khalaf, Reema Abu, Zalloum, Hiba, Al-Bakri, Amal G.
• Format: Article
• Language: English
• Subjects: Acyltransferases - antagonists & inhibitors; Acyltransferases - metabolism; Agrochemicals; Antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Drug Design; Drug development; Drug screening; Drugs; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Fungi - enzymology; Humans; in silico screening; Ligands; Mathematical models; Models, Molecular; Mycoses - drug therapy; NMT; pharmacophore modeling; pharmacophores; QSAR; Quantitative Structure-Activity Relationship; ROC curves; Structure-activity relationships; Survival
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2011.01160.x

N‐Myristoyl transferase is an essential enzyme for fungal growth and survival. The continuous interest in the development of new antifungal agents prompted recent interest in developing new potent inhibitors of fungal N‐myristoyl transferase. In this context, we combined pharmacophore and QSAR modeling to explore the structural requirements for potent N‐myristoyl transferase inhibitors employing 55 known N‐myristoyl transferase ligands. Four binding pharmacophore models emerged in the optimal QSAR equations ( = 0.81–0.83, F‐statistic = 47.89–58.83,  = 0.77–0.80, against 11 external test inhibitors = 0.61–0.71). The successful pharmacophores were complemented with exclusion spheres to optimize their receiver operating characteristic curve profiles. The QSAR equations and their associated pharmacophore models were validated by the identification and experimental evaluation of new promising antifungal leads retrieved from the NCI database and our in‐house‐built database of established drugs and agrochemicals. New potent anti fungal leads we unveiled via pharmacophore modeling and QSAR analysis of fungal N‐Myristoyl Transferase inhibitors followed by in silico screening.