Use of Bioisosteric Replacement Tools to Obtain Mutation-Resistant Antivirals

Mattia CF Prosperi

University of “Roma TRE”

Faculty of Computer Science Engineering

Dept. of Computer Science and Automation (DIA)

via della vasca navale, 79 -00146- Roma

Outline• HIV-1 is a highly mutating

virus which is able to develop quickly resistance to antiretrovirals– Combined treatments (HAART)

are the current choice to lower the viral load to undetectable levels in the body

– Even if the patients’ expected survival time is increased, HIV-1 ultimately can develop cross-resistance

– HAARTs are harmful for the body due to toxicity

Aim

• Mutational pathways of HIV-1 can be explored with respect to natural evolution and under drug pressure– Phenotypic tests, naïve vs

treated population samples• New compounds can be

designed not only to be effective against wild type strains, but also against resistant population

Integration of Techniques• Viral Resistance to commercial Drugs

• Analyses on in-vitro phenotypic tests and Population sampling

• Derivation of different mutational sets

• Huge genomic data base • Los Alamos (more than 27,000

HIV-1 protease sequences)

• Molecular Modelling and Computer Aided Drug Design• HIV-1 protease 3D structure

modelling• Wild type sequences, Mutant

sequences• MOL and Modeller

• Molecular Interaction Fields• Scaffold Hopping

• GRID, SHOP

Results (preliminary)

• Two mutant structures of HIV-1 protease were considered– These structures were

exhibiting opposite phenotypic behaviour for two compounds (SQV and DRV)

• SHOP was able to suggest in both cases the replacement of fragments from one drug to another when considering the mutant structures