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.
Khedkar
Santosh A
SA
Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, India.
Malde
Alpeshkumar K
AK
Coutinho
Evans C
EC
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry*; D004214:Distamycins / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D008956:Models, Chemical; D008958:Models, Molecular; D008962:Models, Theoretical; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D055672:Static Electricity
D000998:Antiviral Agents; D004214:Distamycins; C030000:stallimycin; D004247:DNA
J Med Chem. 2003 Aug 28;46(18):3914-29
12930152
Nature. 1964 Sep 5;203:1064-5
14223076
J Am Chem Soc. 1988 Aug 1;110(18):5959-67
22148765
J Med Chem. 1978 Jul;21(7):607-12
97381
Biosci Biotechnol Biochem. 2006 May;70(5):1060-75
16717405
J Comput Aided Mol Des. 1993 Oct;7(5):587-619
8294948
Science. 2005 Jan 14;307(5707):223-7
15591164
Drug Discov Today. 2002 Oct 15;7(20):1036-8
12546891