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Biomedical subjects

S Chakravarty

Publications and source records attributed to S Chakravarty.

At least 55 records · Page 3Linked to original sources
PubMed1995

Antithrombotic agents: from RGD to peptide mimetics.

This review covers the recent advances in the development of highly potent inhibitors of platelet aggregation as potential therapeutic drugs for thrombosis related to cardiovascular and cerebrovascular diseases. The discovery of RGD sequence-directed cell surface receptors (the integrins) has led to extensive research in the development of small RGD containing peptides and their mimetics as antithrombotic agents. These agents work by inhibiting platelet aggregation through competitive blocking of fibrinogen to the platelet surface receptor, GPIIb/IIIa. The pharmacophoric nature of the aspartic acid and arginine side chains of the RGD unit has allowed the development of strategies for rational design, largely based on assumed bioactive RGD conformations and lead optimization. Applications of such strategies, from RGD peptides to peptide hybrids and then to non-peptide mimetics, are described. Also discussed is the important issue of specificity toward GPIIb/IIIa, keeping in view that the RGD unit is a key recognition signal for a variety of cell surface receptors.

Amino Acid Sequence↗
PubMed1994

Drug-protein interactions. Refined structures of three sulfonamide drug complexes of human carbonic anhydrase I enzyme.

N-unsubstituted sulfonamide drugs are widely used for opthalmic disorders. Inhibition of carbonic anhydrase enzyme is believed to be the chief reason for their therapeutic effects. Structures of three such sulfonamide drugs complexed to human carbonic anhydrase I enzyme (HCAI) refined crystallographically at 2 A resolution are reported here. The drug molecules are all bound in the active site of the enzyme, but among themselves show differences in the orientations of the sulfamido groups interacting with the essential zinc ion in the active site. The activity linked solvent molecule coordinated to zinc in the native enzyme is displaced by all the three sulfonamides. The active site loop of Leu198, Thr199 and His200 has been identified to be important for binding of the drug molecules due to their appreciable atomic displacements and intra-molecular hydrogen bonds arising out of their interactions with the sulfonamides. These interactions along with active site charge requirements are proposed to be responsible for the orientational differences of the sulfamido groups and also for differences in the inhibitory powers of the drugs. A hydrogen bond network involving solvent molecules and active site residues His200 and His67 amongst others in the native enzyme, is disrupted upon binding of methazolamide but not in the other two sulfonamides. This is the first crystallographic evidence of the possible involvement of His200 in the inhibition of HCAI. An important role of Thr199 in distinguishing between the substrate and inhibitor binding modes of HCO3- to the enzyme at high pH is also inferred.

Acetazolamide↗
PubMed1994

A proposed model of bradykinin bound to the rat B2 receptor and its utility for drug design.

A putative model of bradykinin bound to the rat B2 receptor was generated using a combination of homology modeling (from the known transmembrane structure of bacteriorhodopsin), energy minimization, molecular dynamics, and a two-stage conformational search as a docking simulation. Overall, the proposed bound ligand adopts a twisted "S" shape, wherein a C-terminal beta-turn is buried in the receptor just below the extracellular boundary of the cell membrane and the N-terminus is interacting with negatively charged residues in extracellular loop 3 of the receptor (most notably Asp268 and Asp286). Mutagenesis experiments describing mutations which result in both a loss of bradykinin affinity as well as those which have no effect on bradykinin affinity are in good agreement with the proposed structure. In short, the mutagenesis results and the computational simulations each point to the same region of the receptor as likely to bind bradykinin. A double mutation, predicted as being likely to have a dramatic effect on bradykinin binding affinity, was confirmed experimentally, adding some validation to the proposed complex. Moreover, a new pseudopeptide bradykinin receptor antagonist (D-Arg0-Arg1-[12-aminododecanoyl]2- Ser3-D-Tic4-Oic5-Arg6) was designed on the basis of the model, and found to have good receptor affinity. Speculation regarding other possible sites for mutagenesis are also described.

Alanine↗