Small Molecule CD4 mimics (SMCM) comprise a class of highly potent HIV-1 entry inhibitors that block the interaction between the HIV-1 envelope glycoprotein gp120 and the T-cell receptor CD4. The SMCM are characterized by a unique SAR: (i) region1 being a p-Cl phenyl ring in the I generation and a p-Cl,m-F phenyl ring in the II generation of our SMCM; (ii) region2 being an oxalamide linker; and (iii) region3 being a variously decorated piperidine ring in the I generation and an indane ring onward in our II generation SMCM. Region1 is inserted in the CD4 binding site on gp120, called F43 cavity by Hendrickson & co. in 1998, region2 is at the cavity vestibule and region3 is solvent exposed. Our efforts in increasing SMCM gp120 binding and antiviral potency have been focused on modifying regions 1/3 to reach conserved residues among the HIV-1 species, to lead to compounds with a higher breath of activity. Region3 modifications have been successful and are still ongoing, whereas we have not been able to deviate from region1 p-Cl,m-F phenyl ring without decreasing SMCM potency. To optimize region1 rationally, we then decided to investigate computationally the solvent effects in the F43 cavity since we noticed that the cavity is hydrated when CD4 is bound wheres it is not when SMCM are bound. The analysis of the hydration sites of the <i>apo</i> gp120 through WaterMap revealed that the water filling the cavity when the CD4 is bound is high in energy and characterized by high enthalpic and entropic contributions, supporting the hypothesis that water displacement by SMCM is contributing significantly to the affinity of region1 for gp120. However, high-energy water displacement could not permit a rationalization of p-Cl,m-F phenyl ring being the optimal moiety in SMCM. We therefore used quantum mechanics/molecular mechanics (QM/MM) followed by pure quantum mechanics (QM) methods to investigate the non-covalent interactions (NCI) between SMCM region1 and the F43 cavity. We found good agreement between the computed △△QM/MM and △△QM energy trend and the experimental △G trend previously measured by Isothermal Titration Calorimetry (ITC), thus validating our approach.

Investigating the importance of region1 in the small molecule CD4 mimics (SMCM) through QM/MM and pure QM methods

254th National Meeting (2017)

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