Compounds Designed to Fit a Site of Known Structure in Human Haemoglobin

Abstract

I The three-dimensional coordinates of the atoms in human haemoglobin are known, and there is a specific site in the deoxygenated form of the protein at which 2,3-diphosphoglycerate (DPG) interacts. 2 Molecular models of this site have been constructed and used to design compounds which should bind to the deoxy conformation and stabilize it. These compounds should thereby promote oxygen liberation, as does DPG. 3 The compounds so designed were found to promote oxygen liberation. Their relative potencies, as assessed by sigmoidal dose-response curves, are in the predicted sequence.

Substituted benzaldehydes designed to increase the oxygen affinity of human haemoglobin and inhibit the sickling of sickle erythrocytes

“…Oxygen saturation curve measurements Human haemoglobin solutions of low phosphate content were prepared as described previously (Beddell et al, 1976;Paterson et al, 1976) and stored as 2 cm3 aliquots at -20°C. Saturation curve measurements on dilute haemoglobin solutions (23 tLM on a tetramer basis, 5.4 ml of solution) were carried out at 37°C in the dissociation mode using a commercially available automatic apparatus (HEMOX-ANALYZER, T.C.S.…”

“…Because of the success in designing dialdehyde compounds to react at the 13-chain terminal amino groups (Beddell et al, 1976) and a report in the literature of certain pyridoxal derivatives reacting at either a-or P-chain terminal amino groups (Benesch et al, 1973) we turned our attention to the a-chain terminal amino region as a design site. Examination of the crystal structure data available at the time (Perutz etal., 1968;Bolton & Perutz, 1970) for horse deoxy and horse met (oxy type) haemoglobins, indicated considerable differences in structure at the a-terminal amino regions of the two forms, although the differences are not as pronounced as at the corresponding 13-terminal amino regions.…”

“…Previous studies in this laboratory (Beddell et al, 1976) have demonstrated the feasibility of designing novel compounds to interact with a receptor site of known structure on a protein molecule and produce a defined physiological effect. The binding site for the natural effector substance, 2,3-diphosphoglycerate (DPG) (Benesch & Benesch, 1967;Chanutin & Curnish, 1967) in the deoxy conformation of human haemoglobin (Arnone, 1972) was chosen as the model receptor site, and a series of bibenzyl dialdehyde derivatives was designed, synthesized and shown to produce the desired effect, i.e.…”

Structure-based design of nonpeptide inhibitors specific for the human immunodeficiency virus 1 protease.

“…There have been several approaches to this problem. One successful path employs interactive inspection of the structures (6)(7)(8)(9)(10). The emphasis in this paper is the complex steric features of macromolecular surfaces (11,12) at the active site of an enzyme.…”

Inhibition of Hemoglobin S Polymerization in Vitro by a Novel 15-mer EF-Helix β73 Histidine-Containing Peptide

“…Furthermore, rational drug design (also known as structure-based drug design) through the use of computer modeling and results of x-ray diffraction is an emerging approach that is revolutionizing the practice of drug discovery. The first anti-sickling molecules designed from receptor-based molecular modeling, the substituted benzaldehyde BW12C (now referred to as 12C79), were described by Beddell et al (9). This drug has reached clinical trials, but analysis of the covalent complex of 12C79 and Hb A showed that this agent binds to the N-terminal amino group rather than the direct interaction sites of Hb S polymers including the β6Val donor site, β85Phe and β88Leu hydrophobic acceptor sites or the β4Thr-β73Asp hydrogen bond.…”