Journal of Computer-Aided Molecular Design, 14: 355–368, 2000. KLUWER/ESCOM © 2000 Kluwer Academic Publishers. Printed in the Netherlands. 355 Research on anti-HIV-1 agents. Investigation on the CD4-Suradista binding mode through docking experiments Fabrizio Manetti a , Federico Corelli a,b,∗ , Nicola Mongelli c,∗ , Andrea Lombardi Borgia c & Maurizio Botta a,b,∗ a Dipartimento Farmaco Chimico Tecnologico, Universit` a degli Studi di Siena, Via A. Moro s.n.c., I-53100 Siena, Italy; b Centro Interdipartimentale per lo Studio di Sistemi Biomolecolari, Universit` a degli Studi di Siena, Via A. Moro s.n.c., I-53100 Siena, Italy; c Pharmacia & Upjohn, Viale Pasteur 10, I-20014 Nerviano, Milano, Italy Received 7 April 1999; Accepted 3 November 1999 Key words: anti-HIV-1 agents, binding mode, CD4, molecular docking, Suradista compounds Summary Sulfonated distamycin (Suradista) derivatives exhibit anti-HIV-1 activity by inhibiting the binding of the viral enve- lope glycoprotein gp120 to its receptor (CD4). With the aim to propose a possible binding mode between Suradistas and the CD4 macromolecule, molecular docking experiments, followed by energy minimization of the complexes thus obtained, were performed. Computational results show that ligand binding at the CD4 surface involves two or three positively charged regions of the macromolecule, in agreement with the results of X-ray crystallographic analysis of a ternary complex (CD4/gp120/neutralizing antibody) recently reported in the literature. Our findings account well for the structure–activity relationship found for Suradista compounds. Introduction Virus infection is initiated by the attachment of a viral particle to a specific receptor on the plasma membrane of the target cell. One of the most striking findings in this field of research is the extraordinary diversity of cell-surface molecules that have been selected by viruses to gain entry into host cells. These receptors include a broad range of glycoproteins with various cellular functions, and also some glycosphingolipids. The identification of viral receptors is of fundamen- tal importance for the development of antiviral drugs that are able to block the infection process before virus entry. One important feature of viral receptor function is that the so-called ‘receptor’ may not be sufficient by itself for allowing virus entry into the host cell. In the case of CD4, it has recently become evident that one or several cellular accessory factors are needed for ∗ To whom correspondence should be addressed. E-mail: Corelli@unisi.it, Botta@unisi.it, nicola.mongelli@eu.pnu.com the post-binding events leading to the fusion between HIV-1 and the surface of the target cell [1]. In addition, it is now evident that some viruses are able to use more than one cellular receptor. For example, the surface-envelope glycoprotein gp120 of HIV-1 recognizes both the CD4 glycoprotein and the glycosphingolipid galactosylceramide in two different regions. Two of the most relevant aspects of HIV infection that have been intensely studied are: (1) the way in which HIV is transmitted and the mechanisms of viral pathogenesis; (2) how can we prevent or reduce trans- mission and render HIV less pathogenic to the host [2–4]. HIV transmission and pathogenesis are very closely related to the viral envelope glycoproteins. In the CD4-dependent pathway of entry, virus bind- ing takes place at the cell surface and is the result of a highly specific interaction between the princi- pal HIV cellular receptor (the CD4 molecule) and the surface envelope viral glycoprotein gp120 [5]. Sub- sequently, the fusion between the viral envelope and