CoMFA study of distamycin analogs binding to the minor-groove of DNA: a unified model for broad-spectrum activity

A 3D-QSAR analysis has been carried out by comparative molecular field analysis (CoMFA) on a series of distamycin analogs that bind to the DNA of drug-resistant bacterial strains MRSA, PRSP and VSEF. The structures of the molecules were derived from the X-ray structure of distamycin bound to DNA and were aligned using the Database alignment method in Sybyl. Statistically significant CoMFA models for each activity were generated. The CoMFA contours throw light on the structure activity relationship (SAR) and help to identify novel features that can be incorporated into the distamycin framework to improve the activity. Common contours have been gleaned from the three models to construct a unified model that explains the steric and electrostatic requirements for antimicrobial activity against the three resistant strains

Structure–Activity Relationships and Mechanism of Action of Small Molecule Smoothened Modulators Discovered by High-Throughput Screening and Rational Design

Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation or inhibition is considered a potential powerful tool in regenerative medicine and for the treatment of cancer. In the last years, many natural and nonnatural small molecules have been identified that are able to modulate the Hh pathway. Most of them target Smo, while only a few compounds are able to interact directly with upstream and downstream Hh pathway components. Although several compounds showed a remarkable potency and selectivity, their use induced emergence of mutated and resistant cell lines. In an attempt to find new chemical entries able to affect the Hh pathway and overcome limitation imposed by mutations and resistance, academic researchers and pharmaceutical companies are making further efforts to identify new drug-like small molecules to be included in the currently available therapeutic protocols for several types of cancers or in regenerative medicine and tissue repair