QSAR and Molecular Modeling Studies of HIV Protease Inhibitors

  • Rajni GargEmail author
  • Barun Bhhatarai
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 3)


Acquired immunodeficiency syndrome (AIDS) and its related disorders, caused by retrovirus human immunodeficiency virus (HIV) are a major health concern worldwide. HIV protease is one of the major viral targets for the development of new chemotherapeutics. Currently, many HIV protease inhibitors are used in combination with HIV reverse transcriptase inhibitors. However, the use of current drugs regimens has several shortcomings, such as adherence, tolerability, long-term toxicity and drug- and cross-resistance. HIV is also known to have several mutants. Therefore, the development of new inhibitors that are less toxic, more tolerable, convenient and active against drug-resistant viruses is highly desirable. Several in-silico techniques are utilized in the process of drug design and development. One such technique is quantitative structure-activity relationship (QSAR). QSAR models reveal significant correlations between the biological activity and physico-chemical parameters and molecular descriptors. QSAR model can stand alone, support other approaches or be examined in tandem with equations of a similar mechanism to truly reveal its power. This work is devoted to a discussion of QSAR and molecular modeling studies especially those pertaining to 3D-QSAR on HIV protease inhibitors. It provides an overview of new ideas and their applications as they appear in the recent literature. Examples are given of peptidic and non-peptidic protease inhibitors. The role of hydrophobic, steric and electronic interactions in the design of HIV protease inhibitors is discussed. Linking a non-peptidic moiety to a peptidic backbone may provide a way of highlighting regions of interest. Some studies on such hybrid inhibitors are also discussed. Finally, studies on mutant protease data are included as they appear to be of utmost importance.

AIDS HIV protease inhibitors QSAR Molecular modeling Heterocyclic drugs 



acquired immuno deficiency syndrome


human immunodeficiency virus




protease inhibitors


peptidomimetic protease inhibitors


non-peptidic protease inhibitors


structure-activity relationship


quantitative structure-activity relationship


computer aided drug design


comparative molecular field analysis


comparative molecular similarity analysis


minimum concentration of a compound leading to 50% inhibition of the enzyme

EC50 or ED50

the concentration of a compound required to achieve 50% protection of MT-4 or CEM cells against the cytopathic effect of the virus


concentration of a compound required to reduce the number of mock-infected MT-4 or CEM cells by 50%


enzyme inhibition constant


logarithms of inverse of biological end-points

C log P

calculated logarithm of octanol-water partition coefficient P


hydrophobic constant of the substituents

σ, σ & σ+

Hammett electronic parameters of the substituent effects on aromatic systems


Taft's electronic parameters for aliphatic systems


Taft's steric parameter


McGowan volume


van der Waals volume


molecular weight

B1, B5 & L

Verloop's sterimol parameters for substituent width and length


calculated molar refractivity


multiple linear regression


number of data points


correlation coefficient


standard deviation


Cramer's coefficient for the variance in the activity


ratio between the variances of observed and calculated activities

log P0

optimum C log P


partial least square




substructure molecular fragment




United States Food and Drug Administration


transition state isosteres


comparative binding energy analysis


3(S)-amino-2(S)-hydroxyl-4-phenyl butanoic acid


reverse protein-based CoMFA


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This work was supported by grant 2 R15 GM 069323-02 from NIH/NIGMS. We are thankful to Disha Patel and Raghava Kasara for their help in the preparation of the MS. Every attempt has been made to make this work as complete as possible. However, sincere apology is extended if any pertinent work(s) was inadvertently omitted from this review.


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Authors and Affiliations

  1. 1.Chemistry DepartmentClarkson UniversityPotsdamUSA

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