title: Effect of varying chain length between P(1) and P(1') position of tripeptidomimics on activity of angiotensin-converting enzyme inhibitors.
abstract: One of the efficient modes of treatments of chronic hypertension and cardiovascular disorders has been to restrain the formation of angiotensin-II by inhibiting the action of angiotensin-converting enzyme (ACE) on angiotensin-I. The efforts continue towards achieving superior molecules or drugs with improved affinities, better bioavailability and thus to achieve long duration of action with minimum side effects. Previously, we reported a library of tripeptidomimics of Ornithyl-Proline (Orn-Pro) conjugated with various unnatural amino acids and carboxylic acid derived heterocyclics based on the SAR studies of existing ACE inhibitors. Their synthesis and screening for possible inhibitors of angiotensin-converting enzyme (ACE) revealed that increase in the backbone chain length by one carbon atom results in a sudden decrease in their activity. Therefore, in the present study heterocycles with different chain length were introduced to interact with the hydrophobic S(2) sub-site of ACE and screened for their in vitro ACE inhibition activity. Further, their binding interaction with C-domain of somatic ACE was also determined. Docking and consequent LUDI scores showed good correlation with binding of these molecules in the active site of ACE. Results suggest that heterocycles with C(3) chain length are more appropriate for the effective binding of the tripeptidomimics within the active site of ACE.
authors.affiliation: Peptide Synthesis Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi 110 007, India.
authors.forename: Snehlata
authors.initials: S
authors.lastname: Chaudhary
authors.forename: Ishwar Dutt
authors.initials: ID
authors.lastname: Vats
authors.forename: Madhu
authors.initials: M
authors.lastname: Chopra
authors.forename: Parbati
authors.initials: P
authors.lastname: Biswas
authors.forename: Santosh
authors.initials: S
authors.lastname: Pasha
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D002244:Carbon / Q000737:chemistry; D020134:Catalytic Domain; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D010455:Peptides; D013876:Thiophenes; D002244:Carbon