The discovery of HIV and the study of molecular mechanisms crucial for the virus
replication cycle have led to the identification of important protein structures - potential
targets of drug action in AIDS therapy. One of the most significant discoveries is HIV-1
protease (PR), an enzyme that plays a key role in the HIV replication cycle (1). This study
aimed to test and demonstrate the interactions of newly synthesized chalcones (1,3-diaryl-2-
propen-1-one) as well as three commercial drugs (lopinavir, ritonavir and darunavir) in the
active site of HIV-1 protease using in sillico methods. and that the results obtained correlate
with the results of in vitro tests on the enzyme itself. The twenty structurally similar
chalcone derivatives were synthesized and their physico-chemical characterization was
performed. Docking calculations were performed using the Autodock Wine program in the
3D structure of the enzime catalytic site (pdb code: 6B36). The inhibition of enzyme activity
was monitored by fluorimetric method (2). The obtained results revealed that all compounds
showed anti-HIV-1 protease activity. Compound C1 showed the highest inhibitory activity
with an IC 50 values of 0.001 μM which is comparable with commercial product Darunavir.
The results obtained indicate that the synthesized compounds can be classified as potential
anti-HIV-1 protease inhibitors. Further research is focused on testing the ADMET properties
of the synthesized compounds as well as the synthesis of their analogues for which in silico
tests have shown satisfactory results.Otkrić e HIV-a i istraživanje molekularnih mehanizama ključnih za ciklus replikacije
virusa dovelo je do identifikacije važnih proteinskih struktura - potencijalnih ciljnih mesta
dejstva lekova u terapiji AIDS-a. Jedno od najznačajnijih otkrića je HIV-1 proteaza (PR),
enzim koji ima ključnu ulogu u ciklusu replikacije HIV-a (1). Ova studija imala je za cilj da
primenom in sillico metoda ispita i prikaže interakcije novosintetisanih halkona (1,3-diaril-2-
propen-1-ona) kao i tri komercijalna leka (lopinavira, ritonavira i darunavira) u aktivnom
mestu HIV-1 proteaze i da dobijene rezultate koreliše sa rezultatima in vitro testova na
samom enzimu. Sintetisano je dvadeset strukturno sličnih derivata halkona i izvršena
njihova fizičko-hemijska karakterizacija. Docking studije izvedene su u programu Autodock
Vine u 3D strukturi enzimskog katalitičkog mesta (pdb kod: 6B36). Inhibicija enzimske
aktivnosti određena je primenom fluorimetrijske metode (2). Dobijeni rezultati ukazuju da
svih 20 jedinjenja ispoljava anti-HIV-1 proteaznu aktivnost. Jedinjenje HNT1 je pokazalo
najveć u inhibitornu aktivnost sa vrednostima IC50 od 0,001 μM što je uporedivo sa
komercijalnim proizvodom darunavirom. Dobijeni rezultati ukazuju da se sitetisana
jedinjenja mogu klasifikovati kao potencijalni anti-HIV-1 proteazni inhibitori. Dalje
istraživanje je usmereno na ispitivanju ADMET osobina sintetisanih jedinjenja kao i sintezi
njihovih analoga za koje su in silico ispitivanja pokazala zadovoljavajuće rezultate.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra
