Ligand Receptor Recognition

3.4. Ligand Receptor Recognition

It is, however, pertinent to mention here that steric* complimentarily is an absolute necessity, but certainly not a sufficient evidence for ultimate recognition. It is indeed regarded to be a second-order effect, and do not represent a dominant one.

Fig. 3.3. Diagramatic Sketch of Complimentarity in Ligand Receptor Recognition (a) Illustrating shape complimentarity (b) Depicting electrostatic complimentarity

(c) Showing hydrogen-bonding complimentarity.

Figure 3.3 (a, b, c) depicts the three recognized complimentarity** with regard to shape, electro- static status, and hydrogen-bonding diagramatically.

The three aforesaid complimentarity (or similarity) may be legitimately confined to steric aspects (i.e., shape), electrostatic status (i.e., distribution of –ve and +ve charges within the ligand-receptor system), and finally the hydrogen-bonding (i.e., hydrophobic characteristic feature of the system).

Salient Features : The various salient features with respect to the ligand-receptor recognition

are as stated under : (1) Dynamic uneasiness prevailing in the ligand-receptor structures together with the

conformational flexibility of the target and the drug is extremely vital and important. *Concerning the spatial arrangement of atoms in a chemical compound.

*Similarity.

MOLECULAR MODELING AND DRUG DESIGN

(2) The resulting bound conformation of the ‘drug molecule’ need not necesarily be having the minimum energy conformation.

(3) Presence of water molecules* at the ‘active site’ also play a vital role ; and, therefore, must

be taken into consideration positively.

(4) Presence of ‘multiple binding sites’ strategically located in a ‘ligand at the active site’ invariably poses an important subject for due cognizance.

3.5. Active Site for a Target Molecule

C HAPTER

It is an usual practice to identify and subsequently find out the active-site for a target molecule, namely :

• Alpha-shape method

• Density difference method • Filting circles, spheres, rectangles, squares etc.

Interestingly, each one of the aforesaid methods finally gives rise to a certain ‘score’ rightly based upon the most befitting actual quantum of amino acid side chain(s) that occupy inside the ‘active cavity’. However, the available stored genetic modification data is found to be extremely beneficial in the accurate and precise location of the so called ‘active site’. It is worth while to state here that the ensuing ‘active site’ (or ‘envelope’) needs to be defined explicitely before the actual usage of any technique. One may come across a host of altogether different binding sites which really renders the actual selection process a little difficult and cumbersome. It has been established beyond any reasonable doubt that the ligand binding site may also be able to accomodate an appreciable degree of dissimi-

larity present in the ensuing ligand structure, as could be seen in HIV protease, designated as HIV

PR, Figure : 4(a) and (b). Salient Features : The salient features of HIV PR are as enumerated below : (1) It is one of the several strategies that has been proposed to cure and arrest the AIDS phenom-

enon.

(2) It is considered to be absolutely necessary for the viral assembly and subsequent maturation. (3) Scope of further meaningful antiviral therapy via two other enzymes viz., HIV reverse

transcriptase and HIV reverse integrase, may be accomplished by using these structures skillfully.

(4) 3D structures of HIV PR and reverse transcriptase have been duly established, whereas the corresponding structure of the integrase is being investigated.

(5) Design of inhibitors for HIV PR has been a major domain of active and progressive research in a plethora of academic and pharmaceutical research laboratories.

(6) As HIV PR ascertained to be a member of the specific aspartic proteinase family, the legitimate progress has been accomplished in a relatively short span of time.

(7) Valuable information(s) derived via the actual design of significantly small, potent, and bioavailable renin inhibitors based upon the 3D structures of the ensuing aspartic proteases has virtually paved the way towards the tremendous task for designing inhibitors for the HIV PR.

*The ‘water molecules’ very much trapped at the active site.

MEDICINAL CHEMISTRY

(8) HIV PR has ten binding pockets located strategically in the binding site, which ultimately cleaves eight different peptide sequences having wide structural variations. Importantly, a slight, spe- cific, and significant modification in one sequence only may ultimately produce an effective inhibitor.

Fig. 3.4. Ribbon Representation of HIV-Protease Structure (a) HIV PR Enzyme ; (b) HIV PR Enzyme Inhibitor Complexed [Adapted From : Fitzgerald PMD et al.J. Biol Chem. 265, 14209, 1990]

Obviously, the most valuable qualitative information may be discerned by means of not-so- complicated screening of resulting complexes by making use of advanced molecular graphics ; and,

71 therefore, one may accomplish substantial improvement of the ‘known ligands’ through meticulous inves-

MOLECULAR MODELING AND DRUG DESIGN

tigative search for desired accessory binding interactions in terms of ligand modification. Evidently, this particular scientific approach ultimately yielded an exceptionally good dividend through wonderful designing of newer drug molecules at Burroughs-Wellcome Laboratories (UK), such as :

(i) Dihydrofolate Reductase (DHFR) Antagonists — giving an increased affinity, and

(ii) 2, 3-Diphosphoglycerate (DPG) Analogues — regulating the O 2 binding to hemoglobin.